Dynamic crosstalk between HSCs and liver microenvironment: multicellular interactions in the regulation of liver fibrosis

Liver fibrosis is induced by persistent stimulation of various factors, resulting from complex multicellular interactions and multifactorial networks. Without intervention, it can progress to cirrhosis and even liver cancer. Current understanding suggests that liver fibrosis is reversible, making it crucial to explore effective therapeutic strategies for its alleviation. Although the activation and proliferation of hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, the importance of hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs) and immune cells cannot be ignored, the interactions of these cells with HSCs are worth discussing. Therefore, based on the diversity of cell composition in the liver organ, this review summarizes the impact of the parenchymal and nonparenchymal hepatic cells on liver fibrosis, including hepatocytes, cholangiocytes, hepatic macrophages, T cells, NK cells, B cells and LSECs, as well as the fibroblast subpopulations. And further discussed the interactions of these cells with HSCs and illustrated intercellular signal transduction among these cells in contributing to liver fibrosis. Clarifying the roles and interactions of various cells in the development of liver fibrosis will be helpful to explore effective strategies for the treatment of liver fibrosis.

1 Introduction

Liver fibrosis is induced by the chronic and persistent stimulation of various factors such as liver injury, resulting in an imbalance between damage and repair. The activation of hepatic stellate cells (HSCs) is considered to be one of the key events, which in turn contributes to the accumulation of extracellular matrix (ECM). Liver fibrosis does not occur as a result of the independent action of individual cells, but as a complex multicellular network. Although the activation and proliferation of HSCs play a pivotal role in liver fibrosis, the importance of hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs) and immune cells cannot be ignored.

It has been shown in the early state of liver injury, the damaged or dead hepatic parenchymal cells (hepatocytes) are able to release nucleotides, reactive oxygen species (ROS), Hh ligands, and damage-associated molecular modules (DAMPs), which interact with HSCs in the interstitium (Tsuchida and Friedman, 2017). In addition to HSCs, all nonparenchymal cells in the liver also play a role in the occurrence of hepatic fibrosis mediated by HSCs through their secretory substances. Of which, cholangiocyte are involved in biliary fibrosis, which is related to hepatic fibrosis. Various factors like infection, cholestasis and ischemia can stimulate cholangiocyte activation (O'Hara et al., 2017), leading to ductular reaction (DR) and interact with hepatic fibrosis. Macrophages are considered to be central regulators among the immune cells associated with liver fibrosis. Macrophages can regulate the homeostasis of hepatic fibrosis and even cause regression of hepatic fibrosis by secreting matrix-degrading enzymes such as matrix metalloproteinases (MMP) (Tacke and Zimmermann, 2014). Macrophages have a heterogeneous phenotype because they owns highly plasticity in their response to local environmental stimuli. The liver is the site of accumulation of many innate lymphocyte populations (ILTCs), including natural killer cells (NK), CD56 (+) T cells, natural killer T cells (NKT), γδ T cells, and mucosa-associated invariant T cells (MAIT), the latter three of which belong to unconventional T cell subsets. The heterogeneity of T cells and the wide variety of effectors which include various ligands and cytokines, play an important role in the development of liver fibrosis, and they are involved in a close and complex crosstalk with HSCs activation. B cells are a key component of the adaptive immune system, providing specific and long-lasting protection against a large number of potential pathogens through the production of highly diverse and specific antibodies (Visentini et al., 2022), while they can also progressively exacerbate the disease through the secretion of pro-inflammatory factors, antibodies, and the recruitment of other cells. In the human liver, B cells comprise only 8% of the intrahepatic lymphocyte population (Patel et al., 2021). Although there are only a small number of B cells, they also are important in the development of liver diseases. In injured liver, the differentiation of LSECs into capillarization initiates and the inhibition of HSCs activation is reduced to a lesser extent. Depending on the injury, LSECs are able to promote either hepatocyte regeneration or liver fibrosis (Xie et al., 2012).

The occurrence of liver fibrosis is a complex process involving multiple cells. Considering the diversity of cell composition in the liver organ, clarifying the roles and interactions of various cells in the development of liver fibrosis is helpful to explore effective strategies for the treatment of liver fibrosis (Figure 1).

Figure 1

Figure 1. Overview of the interactions of various hepatic cells in the development of liver fibrosis.

2 Interaction of HSCs with hepatocytes

2.1 Hepatocytes

DNA released from hepatocyte apoptotic body can interact with Toll-like receptor (TLR) 9 in HSCs to promote HSCs activation (Watanabe et al., 2007). High Mobility Group Box-1 (HMGB1) and DAMP released from necrotic hepatocytes, activates HSCs by regulating autophagy of HSCs (Li et al., 2018). In hepatocellular carcinoma (HCC), elevated HMGB1 released from gluconeogenic enzyme fructose 1,6-bisphosphatase (FBP1)-deficient hepatocytes triggers HSCs activation. Subsequently HSCs exhibit a senescence-associated secretory phenotype as a result of high levels of senescence-promoting CCN1, which contributes to HCC progression (Li et al., 2020) (Figure 2).

Figure 2

Figure 2. Communication between hepatocytes and HSCs.

Nucleotide-binding oligomerization domain (NLRP3), a downstream effector of DAMPs in the inflammasome. In mice with mutant NLRP3, the hepatocyte cellular pyroptosis and HSCs activation were observed (Tsuchida and Friedman, 2017). In several liver injury models, injured hepatocytes are capable of releasing P2Y14 ligands, such as UDP-glucose and UDP-galactose, which activate the ERK and YAP signaling pathways mediated by the P2Y14 receptor to induce HSCs activation. This interaction lays the foundation for the pro-fibrotic DAMP-DAMP system (Mederacke et al., 2022). Mitochondria of damaged hepatocytes releases mito-DAMPs (mitochondria-DAMPs) which facilitate nonalcoholic steatohepatitis (NASH) inflammation via TLR9, and eventually exacerbate ischemia-reperfusion injury (Garcia-Martinez et al., 2016). Mt-DNA, the bioactive component of mito-DAMPs, activates HSCs released by hepatocytes to promote liver fibrosis. Mito-DAMPs are able to enter the circulation from the local microenvironment and are expected to serve as a biomarker of non-alcoholic fatty liver disease (NAFLD) in humans (An et al., 2020) (Figure 2).

Extracellular vesicles (EV) play an important role in hepatocyte and HSCs communication. It has been demonstrated that toxic lipid overload leads to the release of miR-128-3p-containing EV from hepatocytes. Upon internalization by HSCs, miR-128-3p inhibits PPAP-γ expression and promotes HSCs activation (Povero et al., 2015). Similarly, lipotoxic hepatocyte-derived exosomal miR-1297 promotes HSCs activation through PTEN pathway (Luo et al., 2021). EVs responsible for iron secretion from hepatocytes cause hepatocytes iron deficiency, hepatocytes iron deficiency and HSCs iron overload are features of NAFLD and NASH (Britton et al., 2018). Iron deficiency in hepatocytes facilitate the HIF-2α-ATF4 signaling pathway to promote lipogenesis. RAB27, a small GTPase critical for exosomes secretion, was increased in human NASH/NAFLD. Due to the reduction of Kupffer cells (KCs) in NASH, iron-containing EVs are phagocytosed by HSCs, resulting in HSCs iron overload, which enhances the accumulation of ROS in HSCs and promotes HSCs activation (Gao et al., 2022). ARRB1 (β-arrestin 1), a scaffolding protein in the intracellular signaling network, is involved in the regulation of autophagic flux in HCC (Lei et al., 2021). ARRB1 promotes liver fibrosis by hampering the autophagic lysosomal/multivesicular body pathway by activating Rab27a through p38 MAPK/ATF2 signaling (Liu X. et al., 2023). In addition, hepatocyte-derived EVs can deliver histone 2A family member J (H2AFJ) to HSCs, promoting HSCs activation through the MAPK/STMN1 axis (Liu B. et al., 2023) (Figure 2).

Besides DAMPs and EVs, bioactive molecules are another factors secreted by hepatocytes to regulate HSCs activity. NINJ2 encodes the cell adhesion molecule, nerve injury-inducible protein 2 (Ninjurin2), which modulates vascular endothelial cell activation and inflammatory responses, affecting atherosclerosis and coronary artery disease (Wang J. et al., 2017). In a model of MCD-induced liver fibrosis, NINJ2 knockdown attenuated liver fibrosis. Consistently, hepatocyte-specific NINJ2 overexpression was able to interact with IGF1R in hepatocytes, regulate PDGF-BB expression via the IGF1R-PI3K-AKT-EGR1 pathway, and promote HSCs activation via a paracrine manner, thus accelerating fibrosis in mice (Wang Y. et al., 2023). Forkhead box O protein 1(FoxO1), is a vital factor that participates in the insulin-PI3K-AKT signaling pathway in hepatocytes and regulates cell growth and metabolism (Barthel et al., 2005). FoxO1 was upregulated in a CCl4-induced mouse model of hepatic fibrosis, and knockdown of FoxO1 resulted in significantly reduced TGF-β1 secretion by hepatocytes, which impeded HSCs activation induced by paracrine TGF-β1 (Pan et al., 2024). OPN, a glycolipid protein highly expressed in the liver. E4-binding protein 4 (E4BP4), an important factor in NK cell development and immune regulation, has been reported to take part in the regulation of lipid metabolism (Zhao et al., 2021). In mice with hepatic fibrosis, TGF-β induced E4BP4 expression, which stabilized YAP independently of Hippo pathway, and promoted OPN expression, which caused HSCs activation via paracrine action. Consistent with the described results, the E4BP4 knockout model was reported to show alleviate hepatic fibrosis induced by diet in mice (Wang et al., 2024). Moreover, hepatocyte-secreted osteoblasts (Ma et al., 2023), IL-33 (Yu et al., 2024), and Monocyte-chemoattractant protein-induced protein 1 (Pydyn et al., 2024) also participate in the crosstalk between hepatocytes and HSCs in a similar manner (Figure 2).

Hepatocyte-macrophage-HSCs axis was reported to contribute to HSCs crosstalk. In NASH, macrophages connect hepatocytes with HSCs activation through exocytosis. In liver injury, apoptotic hepatocytes release soluble “find me” signals (ATP, S1P, and CX3CL1) to recruit macrophages, which are subsequently triggered to phagocytose apoptotic cells by phosphatidylinositol on the apoptotic cell membrane (Meadows et al., 2019). In NASH, hepatocyte necrosis is of much significance. CD47, the “don’t eat me” signal, is upregulated in necrotic hepatocytes. At the same time, SIPRα, the receptor for CD47, is also upregulated on macrophages, accompanied by an inhibition of macrophage clearance of necrotic hepatocytes. In vitro experiments and proof-of-concept mouse models, both anti-CD47 and SIPRα measures were administered, and increased macrophage phagocytosis of necrotic hepatocytes was shown, concomitant with mitigated liver fibrosis in vivo. These results suggest that blocking the CD47-SIRPα axis might be an effective strategy for the NASH (Shi et al., 2022). Gentiopicroside has been reported to inhibit the TLR4 and NLRP3 signaling pathways in macrophages, which brought the release of inflammatory factors, improvement of hepatocyte pyroptosis, and alleviation of the hepatic fibrosis (Yong et al., 2024). In a thioacetamide-treated mouse model, the expression of liver fibrosis markers and inflammatory responses mediated by macrophages was suppressed after the inhibition of HMGB1, TLR4 and the assembly of NLRP3/ASC inflammasomes induced by LPS/ATP in mouse peritoneal macrophages (Yao et al., 2024).

In addition, bile acids are also involved in the crosstalk between hepatocytes and HSCs. Sodium+/taurocholate cotransporting polypeptide (NTCP), a multichannel membrane transporter of the hepatocyte within the hepatic sinusoids, is responsible for nearly 90% of the bile acid transportation (Slijepcevic and van de Graaf, 2017; Jani et al., 2018). In bile duct ligation models, bile acids enter hepatocytes via NTCP to induce the expression of cytokines, such as IL-1β, CCL2 and CXCL2 (Cai et al., 2017), enhance neutrophil chemotaxis, and trigger an inflammatory response to initiate liver injury (L et al., 2017). For example, during cholestasis, elevated bile acid concentration can activate MAPK signaling in hepatocytes, which upregulates Egr-1, and thus stimulates neutrophil accumulation and expression of inflammatory cytokines in the liver (Allen et al., 2010). Actually, the function of inflammatory cytokines cannot be ignored in regard of HSCs activities. Moreover, some studies have shown that NTCP is also present on HSCs in patients with liver fibrosis, and the expression level is linearly correlated with the degree of fibrosis. Experimental results showed that NTCP can mediate the uptake of bile acids by HSCs, and in both vivo and vitro experiments, inhibition of NTCP was able to modulate HSCs inactivation (Salhab et al., 2022). Taken all together, bile acids may be able to serve as an important bridge linking hepatocytes and HSCs (Figure 2).

2.2 Interaction of HSCs with hepatocytes

Communication between hepatocytes and HSCs is reciprocal. There are limited studies on the role of exosomes from HSCs in hepatocyte regulation. In TGF-β1-activated LX-2, there is an increase in LX-2-derived exosomes containing miR-199a-5p, which are able to inhibit the proliferation of hepatocyte THLE-2 and promoting its epithelial mesenchymal transition (EMT) and senescence in an autocrine and paracrine manner (Lu et al., 2023). Constantly, it has been substantiated that HSC-derived miRNA-99a-5p in exosomes can suppress hepatocyte proliferation, promote hepatocyte apoptosis, and modulate hepatic fibrosis by targeting BMPR2 (Li F. et al., 2023). In young mouse hepatectomy models, matricellular protein CNN1 was rapidly elevated and induced HSCs senescence (Kim et al., 2013), which promoted HSCs to secrete IL-6 and CXCR2 ligands. IL-6 could activate STAT3 pathway, which induced the activation of the YAP pathway and synergistically activates ERK1/2 with CXCL2 to stimulate hepatocytes proliferation (Cheng et al., 2022). Neurotrophin-3, a profibrotic cytokine derived from HSCs (Wang S. et al., 2023), was reported to induce hepatocyte proliferation by stabilizing CCND1 through activation of the tropomyosin-related kinase B (TRKB) in hepatocytes (Trinh et al., 2023). In the knockdown model of C-type lectin-like transmembrane protein endosialin (EN), which presented on activated HSCs, the expression level of IGF2 was significantly upregulated, accorded with augmented hepatocyte proliferation. The negative effects on hepatocyte proliferation of EN is confirmed (Mogler et al., 2015), but more experimental evidence is required to substantiate the EN-IGF2 axis.

Type 2 diabetes mellitus (T2DM) has a bidirectional and close association with NAFLD/NASH (Younossi et al., 2019; Birkenfeld and Shulman, 2014), and the interaction between hepatocytes and HSCs carries a lot weight. Obesity, insulin resistance (IR), and lipotoxicity dynamically interact, leading to fat accumulation in hepatocytes and resulting in simple lipid storage. Furthermore, the activation and infiltration of hepatic macrophages, dendritic cells, and HSCs induce liver inflammation, thereby promoting the development of liver fibrosis (Mazzoccoli et al., 2018). Additionally, studies have shown that fat overload may render hepatocytes more susceptible to bile acid-induced inflammatory responses and apoptosis (Pusl et al., 2008), while bile acids in the liver may be served as an important bridge linking hepatocytes and HSCs to in the development process of liver fibrosis.

3 Cholangiocyte

In co-culture system, intrahepatic cholangiocytes, proximal intrahepatic cholangiocytes and HSCs all alter gene expression profiles mutually, with enhanced proliferation of intrahepatic cholangiocytes and activation of HSCs through the WNT pathway (Haaker et al., 2025). Although the exact explanation about the interaction between cholangiocytes and HSCs remains unclear, gal, histamine and leptin regulated cholangiocyte as well as HSCs proliferation and activation during cholangitis and fibrosis in MDR2 knockout mice were reported (Petrescu et al., 2020; Jones et al., 2016; Petrescu et al., 2022).

In NASH patients and mice with hepatic fibrosis, it was demonstrated that 12α-OH bile acids significantly activate HSCs via p38MAPK and ERK1/2 signaling pathways mediated by TGR5 (Xie et al., 2021). Transmembrane sphingosine-1-phosphate receptor 2 (S1PR2) plays an important role in cholestasis mediated by bile acids and inflammatory cytokines in vivo (Islam et al., 2024). In the context of cholestasis, it has been shown that taurocholic acid spurs HSCs activation through the S1PR2/p38MAPK/YAP signaling pathway (Yang J. et al., 2023). Previous research has confirmed that taurocholic acid was able to initiate the downstream ERK1/2 and AKT pathways via S1PR2 to facilitate cholangiocyte proliferation (Wang et al., 2017b). Similarly, investigations shown that conjugated bile acids could boost the development of cholangiocellular carcinoma via S1PR2 (Liu et al., 2014). Results above suggest a relationship linked by bile acids between HSCs and cholangiocytes. Besides, in the model of cholestasis, bile acids might be the key factor capable of connecting hepatocytes, HSCs, and cholangiocytes. Moreover, mast cells might mediate the interaction between cholangiocytes and HSCs.

It’s noted that cholangiocytes can express FXRβ and ASBT, imposing the influence of UDCA on the degranulation process in mast cell, in turn affecting HSCs activation (Meng et al., 2018).

The inflammatory cytokine, monocyte chemotactic protein-1 (MCP-1)/CCL2 is a monocyte chemokine released by blood cells. Activated cholangiocytes are able to release MCP-1 to induce the transformation of portal fibroblasts into myofibroblasts and promote their proliferation (Kruglov et al., 2006), as well as to promote the transformation of HSCs (Mühlbauer et al., 2003).

It has been shown that Apelin, the endogenous ligand for the G protein-coupled receptor, is a protein encoded by the apln gene (Tatemoto et al., 1998). The Apelin-APJ axis is involved in renal, myocardial, and renal fibrosis (Lv et al., 2017; Huang et al., 2016). It was demonstrated that in BDL-induced cholestatic liver fibrosis, Apelin-APJ induced cholangiocytes proliferation through Nox4/ROS/ERK signaling, as well as the increase of Col1α1, fibronectin1 (FN1), and TGF-β1 in cholangiocytes, while promoting the proliferation of vascular smooth muscle cells. HSCs activation was also triggered by Apelin-APJ via ROS in paracrine manner during cholestasis (Chen et al., 2021). Meanwhile, study revealed that Notch2, upregulated in the YAP pathway, aids the transformation of hepatocytes into cholangiocytes (Yimlamai et al., 2014). Furthermore, in hepatectomy model in young mice, the biliary tree fails to grow. In the presence of cholestasis, CCN1 spurs the proliferation of cholangiocytes by interacting with integrin αvβ3/αvβ5, inducing the expression of Jag1 via NF-κB, and further activating the NOTCH1 pathway (Kim et al., 2015). Taking the fact mentioned before that CNN1 can induce HSCs senescence into account, CNN1 might be another link between cholangiocytes and HSCs.

In cholestasis model, lncH19 in exosomes from cholangiocytes is preferentially taken up by HSCs rather than hepatocytes, which promotes G1/S conversion, enhances HSCs activation, proliferation, and thus promotes liver fibrosis (Liu R. et al., 2019). Experiment shows that miR-21 upregulation hampers HSCs apoptosis and aggravates hepatic fibrosis in alcoholic liver disease model (Francis et al., 2014). Furthermore, during cholestasis cholangiocytes may secrete exosomes containing miR-21, and therefore increase HSCs activation (Kennedy et al., 2016).

TGF-β/Smad pathway is a classical pathway in HSCs activation, and in cholangiocytes it can elevate the expression of HSC-activating genes. In terms of epigenetic modifications, KAT2A, an acetyltransferase in cholangiocytes, acetylates H3K9 and therefore trigger TGF-β downstream signaling pathways. These signaling pathways increase the expression of genes that assist HSCs activation, such as FN1 and SERPINE1. TGF-β signaling can specifically recruit KAT2A to the promoter regions of these genes, enhancing gene expression through H3K9ac. These gene products are ultimately released by cholanggiocytes in a paracrine manner, promoting HSCs activation as well as the progression of biliary fibrosis (Aseem et al., 2021). Enhancer of zeste homologue 2 (EZH2), an epigenetic regulator involved in the TGF-β pathway in cholangiocytes can directly target and inhibit FN1 in the cholangiocytes, which is an important paracrine factor in regulation of HSCs activation. EZH2 degradation leads to the upregulation of FN1 expression (Jalan-Sakrikar et al., 2019). Above all, these researches indicate the critical role of TGF-β in the communication between HSCs and cholangiocytes.

Crosstalk between HSCs and cholangiocytes is not restricted to themslves. During chronic cholestasis, myofibroblasts HSCs release soluble Hh ligands, which stimulate the expression of chemokine Cxcl16 in cholangiocytes, recruiting monocytes with chemokine cognate receptors, such as NK cells, and orchestrate the repair-related mechanisms of liver inflammation (Omene et al., 2009).

4 Dynamic regulation of HSCs and immune cells

In addition to the HSCs, immune cells including macrophages (Figure 3), NK cells, T lymphocytes, B lymphocytes also play an important role, which can communicate with HSCs to promote or postpone the progression of liver fibrosis (Figure 4).

Figure 3

Figure 3. Hepatic macrophages and HSCs interactions and signaling pathways involved in HSC activation.

Figure 4

Figure 4. Multicellular immunomodulatory network in the process of HSC activation.

4.1 Macrophages/kupffer cells

4.1.1 Hepatic macrophages

Hepatic macrophages can be classified into two groups based on their origin. One group is endogenous resident hepatic macrophages originating from KCs, which make up about 35% of the total number of nonparenchymal hepatic cells. KCs are capable of sensing tissue damage, clearing intestinal pathogens and damaged erythrocytes, and regulating iron and lipid metabolism (Scott and Guilliams, 2018). The other group is bone marrow-derived macrophage (BMDM), recruited from the circulation system, which account for only 5%–30% of the total number of hepatic macrophages. Under homeostatic conditions in the liver, embryonic-derived self-renewing tissue-resident KC tissue predominates. However, when hepatic tissue is damaged, “intravascular sentinel” KC cells are activated in rapid response to extrahepatic perturbations, expressing cytokines and signalling molecules. KCs are exposed to various substances via the portal circulation, and through pattern recognition receptors (PRRs) KCs can sense and remove pathogens (Scott and Guilliams, 2018). PRRs contain at least two families of sensing proteins: the TLRs and the NLRs, including PAMPs and alarmins. The TLRs can recognize bacterial products derived from the intestinal microbiota, such as LPS and peptidoglycan. Chemokines like CCL2, CCL5, CXCL9, CXCL10 and others, as well as their receptors CCD2 (and CCR5) recruit macrophages in circulation into the liver as infiltrating macrophages, which are involved in the inflammatory response and subsequent hepatic fibrosis process (Chazaud, 2014).

BMDM can be transformed into a Ly6c^lo population responsible for tissue remodelling (Ramachandran et al., 2012), with increased expression of MMP, growth factor and phagocytosis-related genes such as MMP9, MMP12, IGF1 and the transmembrane glycoprotein NMB (Gpnmb). BMDM-derived KCs (MoKCs) predominate in the hepatic KCs pool under cholestatic and toxic conditions (Li W. et al., 2023), and show enhanced proliferative and anti-apoptotic properties, while promoting repair and attenuating fibrosis. It is noteworthy that both KCs and BMDM highly express TGF-β, suggesting that both cells contribute to liver fibrosis.

Macrophages consist of heterogeneous subpopulations that exhibit different cellular functions. The current classical paradigm is the M1, M2 subpopulations, which includes classically activated macrophages (M1) and selectively activated (M2) macrophages derived from quiescent M0 macrophages that have undergo diverse differentiation pathways in different microenvironments. M1 macrophages, displaying a pro-inflammatory and anti-tumour phenotype, can present antigens, express cell surface markers such as CD80, CD86, TLR2, TLR4, and secrete pro-inflammatory cytokines, such as TNF-α, IL-6, IL-12, and other factors such as IL-1β, CCL2 and ROS (Shapouri-Moghaddam et al., 2018). In contrast, M2 macrophages display anti-inflammatory and pro-tumour phenotype, expressing arginase 1 and the cell marker CD206. M2 macrophages are capable of secreting anti-inflammatory cytokines such as IL-10, TGF-β, IL-4, and IL-13, and synergistically exerting anti-fibrotic effects (Du et al., 2016). The M2 macrophages can be subdivided into four subtypes: M2a, M2b, M2c, and M2d, where M2a and M2b macrophages mainly promote cell response and immunomodulation of Th2. M2c macrophages can inhibit the immune response and promote tissue remodelling. M2d macrophages mainly promote angiogenesis and tumour progression (Wermuth and Jimenez, 2015). Macrophage polarization is the tendency to convert into a specific functional state in the face of different stimulatory signals in different microenvironments. Inhibition of M1 macrophage polarization and promotion of M2 macrophage polarization are beneficial to the alleviation of liver fibrosis.

However, it is noted that a clear boundary between pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages has not yet been identified. During the pathogenesis process of endometriosis, ectopic endometrium-derived lactate induces polarisation of M2-type macrophages while inhibiting M1-type macrophages (Gou et al., 2023). Besides, M1-type BMDM have shown enhanced therapeutic efficacy in experimental liver fibrosis by modulating the hepatic microenvironment to recruit and modify endogenous macrophages and to regulate NK cell activation (Ma et al., 2017). Conversely, more studies support the existence of novel phenotypic transformation pathways of macrophages in vivo following specific alterations in the tissue microenvironment (Orecchioni et al., 2019).

Single-cell gene sequencing and spatial mapping were used to determine the presence of and isolate a scar-associated TREM2+CD9+ subpopulation of macrophages in the fibrotic ecotone of human cirrhosis. This subpopulation specifically expresses TREM2 and CD9, termed scar-associated macrophages (SAMΦ), and is derived from recruited and differentiated circulating monocyte. It is conserved among species, displays a pro-fibrotic phenotype and expands early in the progression of liver disease (Ramachandran et al., 2019). In contrast, monocyte-derived macrophages (MdM) infiltrating in metabolic dysfunction-associated steatohepatitis (MASH) are heterogeneous, which involves lipid-associated macrophage (LAM) expressing TREM2, Gpnmb, OPN1, CD63 and CD9 (Daemen et al., 2021), one assemble into macrophage aggregates around dying hepatocytes, forming hepatic corona-like structures (hCLS), which localize in areas filled with HSCs to promote fibrosis. In a model of high-fat diet-induced steatosis, specific fibrotic macrophage subpopulations, Ceacaml Msr1 Ly6C+++F4/80 Macl monocytes derived from Ly6C FcεRI-+ granulocyte/macrophage progenitors have been identified, which owns granulocyte characteristics, and was termed isolated atypical monocytes containing a nucleus, which is nucleus-containing atypical monocytes (SatM) (Satoh et al., 2017). Studies have identified NASH-associated macrophages (NAMs) with expression of triggering receptor 2 (Trem2), which is abundant on myeloid cells, by applying single-cell sequence on liver mesenchymal cells in NASH (Xiong et al., 2019). NAMs showed abundant expression of Gpnmb and CD9, which are associated with liver injury and fibrosis.

It is important to note that the relationship between inflammation and fibrosis is by no means “black and white.” Liver fibrosis is a dynamic process, with inflammation and fibrosis being two progressive stages. The inflammatory process not only initiates and maintains fibrosis, but also promote fibrinolysis and fibrosis resolution (Kisseleva and Brenner, 2021). Therefore, it is clear that purely anti-inflammatory and pro-inflammatory effects do not fit well with the different phases of the liver fibrosis. Liver inflammation precedes fibrosis in most liver diseases. And in a range of rodent models, liver fibrosis also induces inflammation.

4.1.2 Hepatic macrophage-HSCs interactions

The activation of HSCs is the central event in liver fibrosis, in which HSCs transdifferentiate into myofibroblasts, losing vitamin A, up-regulating αSMA, and beginning to produce inhibitors of collagen and matrix degradation, leading to excessive ECM deposition. Current research suggests that the activation of HSCs is caused by the inflammatory activity of hepatic immune cells, especially macrophages. Macrophage-HSCs interactions play a key role in the process of liver fibrosis, and exhaustion or blockade of macrophage infiltration reduces HSCs activation and fibrosis (Matsuda et al., 2018). Notably, macrophages impose dual-acting effects on the process and regression of liver fibrogenesis. HSCs are bi-directionally regulated by macrophages. HSCs can be activated by a variety of signals, including cell-cell contacts with macrophages, cytokines derived from activated immune cells, and PAMPs or DAMPs (Tsuchida and Friedman, 2017).

4.1.2.1 Hepatic fibrogenic stage

During the generative phase of liver fibrosis, macrophages produce various mediators that can activate HSCs. KCs, induced by PRRs, NLRP3 in inflammatory vesicles, release various cytokines which trigger the classical TGF-β and PDGF pathways to promote the interaction between HSCs and KCs, further activating HSCs and facilitating the process of liver fibrosis. For example, when binding to LPS, TLR4 induces the production of TNF-α, IL-1, IL-1β and CCL2 to activate myofibroblasts (Wei et al., 2019).

Macrophage-derived TGF-β is thought to be the most potent fibrotic agonist. IL-17 and IL-22 produced by neutrophils and helper T cells 17 (Th 17) can sensitise HSCs to TGF-β stimulation by up-regulating TGF-β receptor II (TGF-βRII), which in turn binds TGF-β on the surface of HSCs, inducing transdifferentiation and activation of HSCs. In turn, activated HSCs produce TGF-β to sustain activation through the feed-forward loop (Hammerich and Tacke, 2023). TGF-β can be deposited in the ECM (‘latent TGF-β’) and activated later by αV integrin-mediated HSCs contraction. CTGF, as a TGF-β downstream factor, mediates the increase of ECM synthesis and secretion (Cai et al., 2018; Trampuž et al., 2023). The main source of CTGF is HSCs, and blocking CTGF significantly inhibits the activation and proliferation of HSCs (Fan et al., 2023). TGF-β has also been found to induce autophagy in HSCs (Zhang J. et al., 2021), and provide energy and nutrients for HSCs activation. Hepatic macrophages, including KC- and BMDM-derived TNF-α and IL-1β, also enhance liver fibrosis by promoting aHSCs survival in an NF-κB-dependent manner (Pradere et al., 2013). But it appears to have no effect on HSCs activation (Pradere et al., 2013). PDGF secreted by endothelial cells and KCs binds to its receptor PDGFR and induces dimerisation and autophosphorylation of its subunits, causing constant activation and proliferation of HSCs (Mortezaee, 2018) (Figure 3).

There is bidirectional regulation and “reciprocity” between HSCs and macrophages. HSCs and macrophages both expressing the nuclear receptor peroxisome proliferator-activated receptor (PPAR), which can lead to a reduction in the activation of both cell types through PPAR γ agonism in HSCs and parallel PPAR δ agonism in macrophages in a mouse model of NASH (Ni et al., 2022) as well as in a clinical trial of 274 NASH patients (Francque et al., 2021; Lefere et al., 2020). In contrast, PPARγ-deficient macrophages exhibit chemotactic, pro-inflammatory and pro-fibrotic features, undergo anti-inflammatory polarisation, and promote IL-1β and CCL2-mediated migration and activation of HSCs associated with the MAPK and NLRP3/caspase-1/IL-1β signalling pathways (Ni et al., 2022). Subsequent administration of the pan-PPAR agonist lanifibranor can significantly ameliorate hepatic fibrosis (Francque et al., 2021). Jagged-1 expressed on liver macrophages and HSCs can interact with Notch1 on HSCs to promote Notch1-mediated HSCs activation and fibrosis (Yang et al., 2019). aHSCs contribute to macrophage migration and activation (Chang et al., 2013), then administration of the pan-PPAR agonist lanifibranor significantly improves liver fibrosis (Francque et al., 2021). aHSCs can assist macrophage phenotypic change to pro-inflammatory and pro-fibrogenic, while p38 inhibition in HSCs abrogates this change (Chang et al., 2013). Large amounts of the non-protein glycosaminoglycan HA are deposited in the ECM in hepatic fibrosis, which can regulate cellular functions via CD44 and TLR4 expressed in both HSCs and macrophages. HSCs are major source of CSF1, which plays a key role in inducing monocyte differentiation and proliferation within the ecotope after loss/exhuastion of KCs, suggesting that there is a reciprocal cycle of interaction between HSCs and KCs (Bonnardel et al., 2019) (Figure 3).

At the same time, PPAR also plays a key role in the development and treatment of T2DM-related NAFLD and is one of the key targets for intervention. PPARs regulate lipid and glucose metabolism, taking an important part in hepatic energy homeostasis and regulation of lipid synthesis. For example, PPAR-α primarily negatively regulates hepatic lipid uptake, PPAR-γ induces insulin sensitization and enhances glucose metabolism, and PPAR-δ regulates metabolism in the liver and other peripheral tissues, which reduces IR (Boyer-Diaz et al., 2020; Bojic and Huff, 2013). Intervention aiming at the PPARs can also alleviate NAFLD. For example, PPAR-α activators, such as certain fibrate compounds can inhibit NF-κB-induced inflammatory genes (Choudhary et al., 2019; Francque et al., 2015). Another example is the antidiabetic drug, pioglitazone, a PPARγ receptor agonist, which can activate the expression of M2-like anti-inflammatory genes in macrophages and restore the M1/M2 polarization (Luo et al., 2017).

Compared to single receptor activation, dual or multi-receptor PPARs activation is more effective, which can cause less side effects, and may even produce opposite effects to single-agent therapy. The dual PPAR-α/δagonist elafibranor (GFT505) has demonstrated efficacy in preclinical models of NAFLD, NASH, and liver fibrosis (Staels et al., 2013). Another case is the activation of PPAR-β/δ, which can reduce the expression of TNF-α or IFN-γ in KCs, thereby inhibiting inflammation. However, PPAR-β activation by L165041 promotes HSCs proliferation in both acute and chronic liver inflammation (Hellemans et al., 2003).

4.1.2.2 Regression stage of liver fibrosis

During the regression phase of liver fibrosis, when underlying liver injury is removed and inflammation subsides, aHSCs can return to a quiescent phenotype, be inactivated, or be removed by apoptosis. Macrophages are a key driver of hepatitis and fibrosis, but they can also adopt a restorative phenotype to support tissue regeneration.

Neutrophils or phagocytes can stimulate macrophage phenotypic switching, leading to increased secretion of anti-fibrotic mediators MMPs, which promotes matrix degradation and regression of liver fibrosis (Popov et al., 2010). Pharmacological inhibition of pro-inflammatory monocyte recruitment using CCL 2 inhibitors in a mouse model of hepatic fibrosis was shown to shift the balance of intrahepatic macrophages towards a restorative phenotype, thereby accelerating fibrotic regression (Baeck et al., 2014). Macrophages in recovering stage also produce anti-inflammatory mediators such as IL-10, IL-4, induce apoptosis of pro-inflammatory macrophages and thus suppress fibrosis (Du et al., 2016). However, it is worth noting that this may only represent an active phenotypic transition and not in a separate subpopulation (Dal-Secco et al., 2015).

MdM, which includes LAM in MASH, exhibits the ability to degrade collagen in the hepatic crown-like structures (hCLS) formed in areas of hepatic fibrosis. HSCs and macrophages are in close contact in the hCLS and can share cytoplasmic contents with adjacent macrophages. HSCs can promote LAM markers such as TREM2, Gpnmb, OPN1, CD63 and CD9 expression, and enhance collagen degradation in macrophages (Chan et al., 2024). In addition, macrophages can induce or activate monocytes or NK cells, upregulate the expression of TNF-related apoptosis-inducing ligand (TRAIL), and promote HSCs apoptosis and collagen degradation (Ma et al., 2017).

In summary, infiltrating monocytes/macrophages can have both pro-fibrotic and anti-fibrotic effects on HSCs in an environmentally dependent manner. The original pro-fibrotic effect turns inhibitory after macrophage exhaustion. But, to complicate matters, macrophage exhaustion promotes further progression of fibrosis when the injury ceases (Duffield et al., 2005). Macrophage exhaustion alone is not the “dividing line” for the initiation of its pro-/anti-fibrotic function.

Related to the above involved cytokines and pathways, a series of drugs have a role in inhibiting the progression of liver fibrosis. Exosomes carrying dihydrofolate reductase (DHFR) play an important role in this process. Exosomes secreted by activated HSCs can further promote M1 polarisation of macrophages, while DHFR silencing in HSCs can reduce Lx-2 activation and M1 polarisation, thereby attenuating the development of liver fibrosis in vitro and in vivo (Peng et al., 2022). Astragalus stellatus (ATB) inhibits HSCs activation, inflammation and EMT through PXR-mediated PINK1/Parkin signalling and modulates HSCs-macrophage crosstalk, thereby alleviating hepatic fibrosis (Dou et al., 2024). Sesamol (SEM), a natural lignan compound isolated from sesame, inhibits hepatic fibrosis by interfering with HSCs-macrophage crosstalk through FXR/LXR axis-mediated autophagy inhibition (Jiang et al., 2024) (Figure 3).

Besides, some modifications to macrophages can also interfere with their communications with HSCs. For example, modification of the chimeric antigen receptor (CAR) of BMDM to form CAR macrophages (CAR-MS) alters their phagocytosis of HSCs, recruits and presents antigens to T cells, and generates specific anti-fibrotic T cell responses to reduce fibroblasts and liver fibrosis in mice (Dai et al., 2024). Lipopolysaccharide modification of clodronate liposomes (CLD-lipos) can effectively exhaust macrophages to significantly increased macrophage clearance and apoptosis of HSCs (Zhang et al., 2024).

4.1.3 The hepatocyte-macrophage-HSCs axis

More than 70% of patients with T2DM are accompanied by NAFLD, and their coexistence and interaction increase the stubbornness of NAFLD. T2DM can promote the progression of NAFLD to NASH via the hepatocyte-macrophage-HSCs axis. Obesity and IR contribute to the onset of T2DM, leading to significant events like lipid metabolism abnormalities, inflammation, and hepatocyte apoptosis (Su et al., 2018). Among these, lipid metabolism abnormalities result in increased lipolysis, fatty acid influxing into the liver, which foster abnormal fat accumulation in the liver, inducing oxidative stress to damage hepatocytes. KCs are activated after ingesting apoptotic fat-rich hepatocytes and free cholesterol, starting pro-inflammatory activation and releasing excessive inflammatory cytokines such as TNF-α, IL-1, and IL-6, facilitating the progression of NAFLD to NASH. Furthermore, KCs lead to activation of HSCs, enhancing liver fibrosis (Su et al., 2018).

Conversely, the inflammatory pathway can interfere with the insulin signaling pathway, leading to a vicious cycle involving obesity, IR, lipid metabolism abnormalities, inflammation, and NAFLD (Ballak et al., 2018). TNF-α can activate its receptor, promoting IRS1 phosphorylation and resulting in IR, which in turn leads to lipid metabolism disorder (Ishizuka et al., 2007). At the same time, TNF-α can also activate downstream inflammatory pathways through the NF-κB signaling pathway (Austin et al., 2008).

4.2 T-lymphocytes of NPCs that are not “NPCs”

The liver is a tolerant organ that releases DAMP, PAMP molecules that activate antigen-presenting cells (APCs) when it is stimulated by multifactorial factors such as bacterial and viral infections and hepatocellular damage. Many of the nonparenchymal cell populations therein act as APCs to present antigens and co-stimulatory molecules to ILTC. ILTC preferentially suppresses adaptive immunity by killing or inactivating T cells or by inducing the maturation of initial T cells into regulatory T cells, or say Tregs that suppress CD4 and CD8 T cell responses. Instead of initiating the activation of T cells, APCs prefer to induce T cell tolerance. APCs upregulates co-inhibiting ligands like programmed cell death-ligand 1(PD-L1) and programmed cell death-ligand 2(PD-L2) after IFN stimulation and produce immunomodulatory cytokines. When negative regulatory signalling in effector cell is defective, the immune system can be activated but pathogen defence fails. The presence of the suppressive pathway maintains immune homeostasis, with self-preserving T-cell exhaustion to prevent over-activation and exhaustion of immune cells, but meanwhile sustains appropriate clearance of pathogens and tumour cells. For example, in chronic hepatitis caused by Hepatitis B Virus (HBV), effector CD8⁺ T cells show a multilayered “exhaustion” phenotype, with a markedly reduced proliferative capacity and the production of IFN-γ, IL-2, TNF-α, granzymes, or perforin (Hoogeveen et al., 2019), which may be associated with the upregulation of co-inhibitory receptors like programmed death 1(PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA) (Isogawa and Tanaka, 2015). The imbalance between effector T cells and Tregs, especially Th17/Tregs, therefore underlies the loss of autoantigenic immune tolerance and plays a key role in the progression of liver fibrosis.

ILTCs in general produce three types of cytokines: type 1 cytokines drive inflammation by initiating the migration of effector cells (Ruf et al., 2021). In contrast, type 2 cytokines such as IL-4 and IL-10 suppress immune-associated cytotoxicity through activation of Tregs or myeloid-derived suppressor cells (MDSC) (Shiri et al., 2024; Yang et al., 2017). Type 3 cytokines such as IL-17 and IL-22 can stimulate HSCs, which can lead to ECM deposition and fibrosis (Zhang et al., 2009).

HSCs also have strong immunomodulatory activities, including suppressing T cells through direct cell-to-cell contact mediated by PD-L1 on the HSCs surface (Charles et al., 2013), and enhancing suppression of T- and B-cell responses by promoting proliferation of myeloid-derived suppressor cells (Li et al., 2014). HSCs can inhibit Treg proliferation by activating latent TGF-β1 in hepatic HSC cells via glycoprotein-A repetitions predominant (GARP), a marker on the surface of activated Tregs (Li et al., 2015). NKT cells can exacerbate hepatic fibrosis by producing IL-4 that induces GARP expression on HSCs. Therefore, targeting ILTC to modulate their functions and interactions with HSCs is important for aiding the treatment of liver fibrosis by restoring immune homeostasis and reducing liver inflammation (Figure 4).

4.2.1 IL-17A mediation

It is an important way that ILTC-associated IL-17A exacerbates fibrosis progression through activation of HSC/hepatic myofibroblasts (HMF). Studies found that MAIT cells isolated from PBMCs of patients with alcohol induced liver disease (AILD) regulated HSCs in vitro and induced a pro-fibrotic phenotype through IL-17 secretion (Böttcher et al., 2018). In a mouse model of arsenite-induced hepatic fibrosis, miRNA-21 disrupts the metabolic reprogramming of CD4 T cells through the PTEN/PI3K/AKT pathway to promote polarisation towards a Th2 phenotype, upregulating pro-fibrotic factors such as the transcription factors GATA binding protein 3 (GATA3), and pro-fibrotic factors like IL-4 and IL-13, thus promoting the activation of HSCs (Sun et al., 2022). Arsenite can downregulate miR-17-5p via HOTAIR, which in turn promotes the nuclear receptor retinoic acid receptor-associated orphan receptor γt (RORγt) and pro-inflammatory cytokine IL-17-mediated differentiation from CD4 T-cells to Th17 cells, which further activate the HSCs and facilitate fibrosis (Wu et al., 2023). Both HSCs and Th17 cells can secrete CCL20, a Th17 chemotactic agent, of which the corresponding receptor, CCR6, is expressed in Th17 and γδ T cells. Therefore, it is likely that CCL20 directly mediates HSCs and Th17 cell recruitment in acute alcoholic hepatitis and fibrosis (Annunziato et al., 2007). Researchers also found that HSCs could upregulate the number of Th17 cells and Tregs in liver tissues of patients with advanced HBV-associated hepatic fibrosis through the PGE2-/EP2 and EP4 pathways (Li et al., 2017). In patients with chronic liver disease, IL-33, the Th2 cell chemotactic agent and alarmin, enhances the recruitment and activation of CD4⁺ T cells with Th2-like properties, which activate HSCs in a paracrine IL-13-dependent manner and promote fibrosis (Reißing et al., 2024).

4.2.2 Receptor mediation

Pattern recognition receptors expressed at high levels on parenchymal and non-parenchymal liver cells are mainly three, the TLR, NOD-like receptor (NLR) and RIG-like receptor (RLR). They recognize microbial components not found in mammalian systems and also play an important role in the interaction of T cells with HSCs to promote liver fibrosis. They recognize microbial components that are not found in mammalian systems and also play an important role in T cell-HSCs interactions to promote liver fibrosis. For example, HSCs can increase the immunosuppressive function of natural Foxp3+ Treg through indoleamine 2,3-dioxygenase (IDO)-induced activation of aryl hydrocarbon receptor (AhR) (Kumar et al., 2017). Self-noncoding RNA-containing exosomes from HSCs can mediate the activation of TLR3, which can further exacerbate hepatic fibrosis by enhancing the production of IL-17A by γδ T cells (Seo et al., 2016). Furthermore, TLR is also a member of the gut-liver axis, and toll-like receptor ligands derived from the intestine can directly affect Tregs function by binding to TLR on the Treg surface and inducing trans-differentiation into non-inhibitory Tregs (Osei-Bordom et al., 2020).

Blocking retinol metabolism is a promising therapeutic target and pathway to protect against T cell-induced hepatitis by increasing Tregs migration. HSCs are rich in retinol, containing 70% of the body’s retinol and play an important role in retinol homeostasis. Semaphorin-4D (Sema4D), which is involved in T-cell initiation and antibody production, is upregulated during HSCs activation. Its knockdown suppresses the homeostasis of Th1, Th2, Th17, and Treg cells through inhibition of the AOX1/retinoic acid receptor-α(RAR-α) pathway in retinol metabolism, which impedes the progression of hepatic fibrosis (Wang L. et al., 2023). HSCs are involved in Tregs expansion and differentiation through IFN-γ-mediated stimulation and Raldh1-derived RA production, respectively (Dunham et al., 2013). In the presence of the wide-spectrum ADH inhibitors 4-methylpyrazole (4-MP) and IFN-γ, HSCs increase the gene expression of CCR2 and IL-10 in Tregs. However, in the absence of Raldh1, HSCs can increase Tregs migration in a CCL2/CCR2-dependent manner, which ameliorates liver injury (Lee et al., 2015). C-AMP responsive element modulator-α (CREMα) is a central mediator of T-cell pathogenesis and contributes to the increase of IL-17 expression in patients with autoimmune diseases. Retinoic acid of HSCs origin induces the Treg phenotype in hepatic T-cells in transgenic mice overexpressing CREMα, leading to Tregs protective response (Kuttkat et al., 2017).

Double-negative T-cells (DNTs) are one of the important immune cells that mediate the progression of liver fibrosis, which can interact with HSCs through the NLRP3 receptor-mediated pathway. Studies found that the proportion of DNTs was increased in patients with liver fibrosis (Yang Y. et al., 2023). The transcription factor AP-4 (TFAP4) promotes the transcriptional expression of OX40, which in turn promotes the differentiation and survival of DNTs through its downstream genes such as NF-κB, Bcl-2, and surviving. And DNTs with high expression of TNF-α promote the activation of HSCs and exacerbate hepatic fibrosis through the TNFR1-NLRP3 (Han et al., 2023).

FasL-Fas is also an important pair of partner. Single-cell transcriptome analysis and fluorescence-activated cell sorter (FACS) analysis of NASH mouse models revealed that hepatic CD8 tissue-resident memory CD8 T (CD8 Trm) cells maintained by tissue IL-15 attracted HSCs in a CCR5-dependent manner and predisposed aHSCs to FasL-Fas-mediated apoptosis (Koda et al., 2021). When HSCs are co-cultured with γδ T cells, γδ T cells can eliminate aHSCs in co-culture through activation of natural cytotoxicity triggering receptor 1 (NKp46), TRAIL, and FasL mechanisms (Liu M. et al., 2019).

In addition, it should not be overlooked that the previously mentioned CTLA-4 family is also a T-cell surface receptor that competitively antagonises the T-cell co-stimulatory receptor CD28 and prevents T-cell activation. PD-1, a member of the CTLA-4 family, plays a similar role to play in maintaining homeostasis of effector T-cell function.

4.2.3 T-cell autophagy

T-cell autophagy has also been recently found to be strongly associated with liver fibrosis. Human hepatic memory CD8+T (TRM) cells have different phenotypes, transcription factor expression, and the ability to maintain effective IL-2 and IFN-γ production in tolerant livers (Fernandez-Ruiz et al., 2016). Primary HSCs or prototypic hepatic secreting cytokine IL-15 induce autophagy in TRM cells in parallel with tissue homing/retention markers to adapt to mitochondrial depolarisation, optimise function and acquire tissue residency (Swadling et al., 2020). Three promising autophagy-associated differentially expressed genes as therapeutic biomarkers for hepatic fibrosis, including autophagy - related 5 (ATG5), retinoblastoma inducible coiled-coil protein 1 (RB1CC1) and PARK2, among which RB1CC1 may promote the progression of liver fibrosis by regulating macrophages, Th17 cells, NK cells and CD56dim natural killer cells (Huang et al., 2024).

4.2.4 Apoptosis and lysis

γδ T cells are an interesting “sword” fighting against the process of liver fibrosis and like to cooperate with NK cells to communicate with HSCs to fight fibrosis. γδ T cells are divided into γδ T1 and γδ T17 functional subpopulations defined by IFN-γ and IL-17 production respectively. γδ T cells express γδ TCRs composed of Vδ and Vγ chains and the TCR pool is diversified through V (DJ) DNA recombination. Even though it can express TCRs it still has innate immune cell characteristics. They can also rapidly sense environmental changes through the expression of integrins, chemokines, and activate the relevant cells in a TCR-independent manner to rapidly generate effective effector responses. In most cases, γδ T cells, especially the γδT1 subpopulation, have a very potent cytotoxic effect on HSCs, by producing IFN-γ (Hammerich et al., 2014), or with the help of chronic hepatitis-promoted expression of NKp46 to directly kill aHSCs (Liu M. et al., 2019), which at the same time increases the cytotoxicity of NK cells against aHSCs to fight fibrosis. In addition, γδ T cells, especially the recently discovered Vγ4 γδ T subpopulation, can lead to adoptive transfer, which directly induces HSCs apoptosis and enhances NK cell-mediated HSCs cytolysis, thus significantly alleviating hepatic fibrosis (Liu M. et al., 2019). γδ T cells also promote the anti-fibrotic capacity of conventional natural killer (cNK) cells and liver resident NK (lrNK) cells while enhancing cytotoxicity against activated HSCs (Liu M. et al., 2019).

4.2.5 Multicellular immunomodulatory network

Tregs can inhibit NK cell activation when co-cultured with HSCs in a cell-contact-dependent manner involving CTLA-4, which in turn inhibits NK cell killing of aHSCs and downregulates natural killer group 2, member D (NKG2D) ligands of NK cell receptor ligands activated on HSCs such as UL16-binding protein-liketranscript 1/UL16-binding protein 2(ULBP-1/2) (Langhans et al., 2015). In NASH livers enriched with C-X-C motif chemokine receptor 6(CXCR6) CD8 T cells with low activity of the forkhead box protein O1(FoxO1) transcription factor, cells can be auto-aggressively killed in an MHC class I non-dependent manner via signals from the P2X7 purinergic receptor. Meanwhile, IL-15 can induce FoxO1 downregulation and CXCR6 upregulation, which together make liver-resident CXCR6 CD8 T cells susceptible to metabolic stimuli, including acetate and extracellular ATP, and collectively trigger self-attack (Dudek et al., 2021). Hepatic macrophages accumulated in CCl4-induced liver injury can produce IL-1β to promote the activation of mTORC2 signalling in γδ T cells, which upregulates T-bet expression and ultimately promotes CXCR3 transcription to drive the migration of γδ T cells. Hepatic γδ T cells have reached destination and can then cause cytotoxicity to aHSCs in a FasL-dependent manner to ameliorate hepatic fibrosis. They can also secrete IFN-γ to inhibit the differentiation of pro-fibrotic Th17 cells (Liu et al., 2022). γδ T cells can promote the anti-fibrotic capacity of cNK cells and lrNK cells by enhancing cytotoxicity against aHSCs. For example, cNK cells can prevent hepatic fibrosis by TRAIL-dependent manner to kill aHSCs (Liu M. et al., 2019). CCR6 γδ T cells accumulate in fibrotic livers in the vicinity of HSCs, which limit hepatic fibrosis by producing IL-17 and IL-22 (Hammerich et al., 2014). In a mouse model of cholestatic liver fibrosis, activated MAIT cells can ameliorate fibrosis by direct cell-to-cell contact and NK cytotoxicity enhanced by TNF-α to HSCs (Jiang et al., 2022).

4.3 NK cells

Nearly half of the lymphocytes in the liver are NK cells, which have a relatively diverse cellular classification with the continuous development of various high-dimensional cellular heterogeneity analysis techniques such as spectral cytometry, time-of-flight cytometry (CyTOF) or scRNA-seq. They can usually be classified into transient cNK cells and lr-NK cells (Mikulak et al., 2019). They can also be further divided into three functional subsets, tolerogenic NK cells, regulatory NK cells and cytotoxic NK cells (Fu et al., 2014). CD11b+CD27- NK cells are likewise immature NKs with differentiation potential, displaying potent cytolytic function, as previously mentioned high cytotoxicity to HSCs (Fu et al., 2011).

Notably, NK cells play a dual role in liver fibrosis. They can promote hepatic fibrosis by producing pro-fibrotic cytokines such as IL-4 and IL-13 (Wehr et al., 2013), while they can also inhibit fibrosis by producing IFNγ to kill HSCs under specific conditions (Park et al., 2009). cNK cells can resist hepatic fibrosis by killing aHSCs in a TRAIL-dependent manner (Liu M. et al., 2019). Meanwhile, in a mouse model of hepatic fibrosis found that retinoid signalling can sensitise HSCs to NK cell killing by upregulating the NKG2D ligand RNA export 1 homolog (RAE1) (Radaeva et al., 2006). In humans, aHSCs can similarly lead to the upregulation of the NKG2D ligands ULBP-1/2 and MHC class I chain-related A/B (MIC-A/B), which can in turn trigger NK cell killing (Glässner et al., 2012).

In addition to the mentioned modulation of receptor-ligand to increase the sensitivity of NK-HSCs recognition to promote NK killing, interference with external factors such as CTLA-4-associated T cells, prostaglandin E receptor 3 (EP3), dihydromyricetin (DHM), microRNA, can help to enhance NK killing of HSCs to inhibit liver fibrosis. In chronic hepatitis liver fibrosis, when CTLA-4 regulatory cells are co-cultured with HSCs, they can secrete cytokines such as IL-8 and TGF-β1 to inhibit the expression of the NKG 2D ligands, MIC-A/B, as well as the expression of HLA class I on HSCs, and thus inhibit the activation of NK cells (Langhans et al., 2015). G-protein-coupled receptor (GPCR) EP3 promotes CD11b+ CD27⁺ NK cells Itga 4-VCAM 1-dependent cytotoxicity of HSCs (Glässner et al., 2012; Tao et al., 2022). PD-1/PD-L1, which balances the function of effector T cells as mentioned, also plays an important role in NK cells. With NK cells dysfunction at later stages of chronic hepatitis, PD-1 as a marker of NK cells exhaustion, is increased, especially in some hepatocellular carcinoma (Peng et al., 2022). DHM enhances IFN-γ expression through the NF-κB/STAT3 pathway to improve NK cell killing, inhibits HSCs activation and significantly improves the CCL4-induced liver fibrosis (Zhou et al., 2021). The expression of CCR2 and IL-10 in Tregs enhanced by HSCs can equivalently inhibit IFN-γ production in NK cells to promote aHSCs apoptosis and inhibit HSCs activation, attenuating liver fibrosis (Yi et al., 2014). In addition, EVs and exosomes often contain a variety of functional miRNAs, which carry out mail-type communication between cells. NK cells can hamper cytotoxic killing of HSCs with the help of miRNAs. miR-233 and miR-96-5p in NK cells exosomes could block autophagy of aHSCs by inhibiting the expression of autophagy-related 7 (ATG 7) (Wang L. et al., 2020; Yu et al., 2018).

However, it is worth noting that some studies have found that the anti-fibrotic activity of NK cells is negatively correlated with the progression of hepatic fibrosis in patients with chronic hepatitis C, which is most likely due to the fact that the large increase in the secretion of TGF-β1 by aHSCs can inhibit the degranulation of NK cells and IFN-γ production, and thus suppress their anti-fibrotic effects (Shi et al., 2017). Moreover, conversely, these new NK cells, instead of fighting HSCs, significantly promoted the proliferation of HSC-T6 or LX-2 cells co-cultured with them, and further increased the expression of collagen type I and α-SMA. Therefore, the duration of different liver injury conditions, in particular, is important for the direction of NK cell properties, rather than simply saying that NK cells maintain a single identity throughout the entire hepatic fibrosis process. So, the interaction between NK cells and HSCs is a promising approach to alleviate liver fibrosis.

Currently, CAR engineering of NK cells is gradually being proven to treat liver fibrosis and HCC with high specificity and few side effects. In the present, allogeneic induced pluripotent stem (iPS) cells were used to conduct CAR-NK cell therapy, a replacement cell for HSCs, and more than 1,340 clinical trials have been conducted by 2021, which is promising for the future (Arias et al., 2021).

4.4 B-lymphocytes

It has been reported that many B cell subpopulations have been identified, including B-1, B-2, and regulatory B cells. B-1 cells are mainly derived from fetal liver, and B-2 cells are derived from bone marrow (BM). Regulatory B cells (Bregs) can suppress the immune response mainly through the production of the anti-inflammatory cytokine IL-10 (Wang Y. et al., 2020). Recent evidence suggests that adaptive immune cells are an important regulatory factor in metabolic dysfunction-associated steatotic liver disease (MASLD). In liver biopsies from patients with MASLD, the accumulation of intrahepatic B cells was positively correlated with MASLD activity scores (Li and Xia, 2024). In addition, intrahepatic B cells may also be involved in MASLD by inducing the secretion of IL-6, TNF-α and IgG2a as well as enhancing the activation of CD4⁺ T cells and their differentiation to Th1 cells (Zhang et al., 2016). Aapelin/APLNR promotes the migration and activation of B cells, which results in the expression of cytokines such as AHNAK, COL6A3, IL10, IRF9 and RFX2, affecting liver fibrosis in MASLD (Jiang et al., 2025). Hepatic B-cell infiltration has been observed in experimental models of MASLD (Li and Xia, 2024). In advanced MASH in humans and mice, IL21 is activated through the IL-21R-STAT1-c-Jun/c-Fos-IgA regulatory pathway, leading to the induction of immunosuppressive IgA+ B cells and the accumulation of IgA-producing plasma cells, which inhibit anti-tumour cytotoxic CD8⁺ T cells through the expression of PD-L1 and IL-10, thus facilitating the emergence of HCC (Sutti and Albano, 2020; Xie et al., 2024). It has been shown that TLR4 ligands can activate B cells through the TLR4-MyD88 pathway, leading to NF-κB stimulation. Also, endogenous DNA-containing antigens released by dying cells can activate B cells via TLR9 (Barrow et al., 2021). In summary, through different pathways, B cells can be activated to produce different antibodies and cytokines, contributing to the development of MASLD and MASH, which may lead to the emergence of liver fibrosis (LF) and HCC.

In autoimmune hepatitis (AIH), autoantibody LKM-1 from B cells can target and recognize CYP2D6 on hepatocytes, which may be directly involved in autoimmune liver injury. Tetraspanin 1 (TSPAN1) B cells secrete a large number of inflammatory cytokines, which suggests their involvement in autoimmune hepatitis liver injury and its progression (Longhi et al., 2024). Corticosteroids, ursodeoxycholic acid, and rituximab have been reported as therapeutic agents for immune-mediated liver disease, where prednisolone and rituximab can act on B cells therapeutically (Cargill and Culver, 2021). B cells are also involved in liver fibrosis. Experiments using single-cell analysis, found that hepatic B cells in CCl4-induced LF were predominantly naïve B cells (more than 98%), which suggests that hepatic B cells function mainly as innate immune cells in the context of the present studies (Feng et al., 2025). In acute chronic liver failure (ACLF) livers resulting from further progression of hepatic fibrosis, the fraction of naive B cells was reduced, and CD27CD21 atypical memory B cells (atMBC) expressing higher CD11c and lower CD80 molecules were abundant. Besides, preferential accumulation of intrahepatic CD27CD38 plasma cells was shown. Expression of greater amounts of CD273 (PD-L2) and secretion of higher levels of granzyme B and IL-10 were observed. These all are positively correlated with disease severity indices (Zhao et al., 2022). As the disease progresses, patients with cirrhosis have lower levels of CD27 MBCs and higher levels of naïve B cells, and these B cells in patients with cirrhosis suffering from more advanced liver disease show a maturation transition towards CD27 MBCs, double-negative B cells and plasmablasts compared to patients with earlier stages of the disease (Cardoso et al., 2021). In this regard, treatment of fibrosis may prevent the disease from deteriorating again.

It has been experimentally shown that HSCs can have an effect on B cells. Using isolated mouse primary HSCs, we found in vitro and in vivo that HSCs directly inhibit B cells via PD-L1, which interacts with PD-1 on B cells to inhibit proliferation and antibody/cytokine production in activated B cells (Li et al., 2016). Retinoic acid produced by HSCs enhances B cell survival, plasma cell marker CD138 expression and IgG production. These activities were reversed when the retinoic acid inhibitor LE540 was administered. Meanwhile, transcriptional profiling in fibrotic hepatic B cells showed increased expression of genes related to NF-κB activation, pro-inflammatory cytokine production and CD40 signalling in activated B cells, suggesting that these B cells are activated and may act as inflammatory cells (Thapa et al., 2015). In turn, B cells can have an effect on HSCs. Surprisingly, B cells can selectively affect ECM production without affecting the number of α-SMA-positive myofibroblasts (Li et al., 2016). Experiments have shown that lymphocyte ablation (especially B cells) strongly inhibits HSCs activation and ECM deposition, and enhances the transition of HSCs to cellular senescence. Conversely, B cells maintain LF and foster the growth of HCC in chronic injury by modulating the innate components of inflammation, limiting the extent of HSCs’ senescence and promoting the pro-tumourigenic TNF-α/NF-κB pathway (Faggioli et al., 2018). This pro-fibrotic function of B cells can be attributed to the elicitation of IL-6 and the helper T 1 (Th1) response, which disrupts ECM renewal in chronic inflammation. Meanwhile, B cells can be pro-fibrotic by activating HSCs through the production of TGF-β1 and TNF-α or by inhibiting ECM degradation through TIMP-2. In addition, B-cell receptor (BCR) restriction reduced B-cell maturation, activation, and effector responses in the liver, accompanied by a reduction in T-cell and macrophage-mediated inflammation. BCR restriction attenuated hepatic fibrosis in mice, which was associated with a reduction in IgG production on HSCs and a decrease in the expression of the Fc-γ receptor (Barrow et al., 2023). What’s more, it has been shown that neuropeptide (NPY) is upregulated in human MASLD and that B cells may require dipeptidyl peptidase 4 (DPP4) to contribute to CCL4-induced hepatic fibrosis via NPY to induce maximal collagen production (Wang XM. et al., 2017).

In summary, we focus on the pro-inflammatory and pro-fibrotic roles of B-cells in the liver, which provides a new research direction for immunotherapy of liver diseases.

5 Interaction HSCs with other stromal cells

5.1 Liver sinusoidal endothelial cells (LSECs)

In acute liver injury, LESCs induce hepatocyte regeneration via CXCR7, whereas fibrosis is mediated by CXCR4 and fibroblast growth factor receptor 1 (FGFR1) in the setting of long-term injury (Ding et al., 2014). Zinc-finger E-box-binding homeobox2 (Zeb2), which is expressed in HSCs and regulates HSCs activation and apoptosis (Zhou et al., 2016; Yang et al., 2018). It was displayed that Zeb2 knockdown promoted LSECs capillarization and affected the expression of genes related to LSECs-HSCs communication. Genes that attenuate fibrosis such as GDF15 (growth/differentiation factor 15), LTF (lactoferrin), and IGF1 are downregulated. Changes in capillarization and gene expression simultaneously promote HSCs activation (de Haan et al., 2022).

In a healthy liver, VEGF mediates NO synthesis by nitric oxide synthase within LSECs to inhibit and reverse HSCs activation (Tsuchida and Friedman, 2017). During fibrosis, VEGF derived from hepatocytes and HSCs maintains the fenestration phenotype of LSECs through the eNOS-sGC pathway and non-NO-dependent pathways (DeLeve, 2015). In fact, capillarization of LSECs precedes the activation of HSCs and macrophages after liver injury (Poisson et al., 2017).

The Notch signaling pathway plays an essential role in maintaining hepatic sinusoidal and hepatocyte homeostasis, whereas the activation of the NOTCH pathway in LSECs inhibits the eNOS/sGC signaling pathway, resulting in the promotion of LSECs capillarization, impairment of liver regeneration, and hepatic fibrosis progression (Duan et al., 2018). Delta-like protein 4 (DLL4), a ligand of the Notch signaling pathway, is highly elevated in LSECs in liver fibrosis. It has been shown that DLL4 overexpression increases endothelin-1 (ET-1) synthesis and enhances HSCs coverage in the hepatic sinusoids (Chen et al., 2019). In the case of portal hypertension caused by cirrhosis, ET-1 was able to strengthen the HSCs contraction, leading to an increased vascular resistance. In the case of stress and chronic liver disease, however, ET-1 encourages HSCs differentiation into myofibroblasts (Kojima et al., 2001). Furthermore, in terms of epigenetic regulation, AIRN is an antisense lincRNA of the nuclear-localized IGF2R that enters the cytoplasm in a stable form after being spliced (Seidl et al., 2006). Kruppel-like factor 2 (KLF2), a transcription factor capable of positively regulating the eNOS-sGC pathway maintains LSECs differentiation, has been demonstrated to facilitate the inactivation of HSCs activation and apoptosis to alleviate liver fibrosis by Simvastatin (Marrone et al., 2015). It has been reported that AIRN negatively regulates HSCs activation by maintaining the normal LSECs phenotype through the KLF2-eNOS-sGC pathway. Meanwhile, AIRN in hepatocytes promotes hepatocyte proliferation via LSECs paracrine secretion of Wnt2a and HGF (Hepatocyte Growth Factor) (Chen et al., 2022) directly and indirectly. POFUT1 is an important regulator in Notch signaling, which can control angiogenesis in coronary artery endothelial cells during embryogenesis (Wang et al., 2017d). Experiments displayed that in the hepatic fibrosis mice model with POFUT1 knockout in LSECs, POFUT1 deficiency inhibited the KLF2-eNOS-sGC signaling axis, promoting injury-induced LSEC capillarization, while up-regulating the expression of fibrinogen in LSEC through the NOTCH/HES1/STAT3 pathway. These fibrinogens may foster HSCs activation by binding to integrin αvβ3/5 on HSCs’ membranes, suggesting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis as a novel therapeutic strategy of liver fibrosis (He et al., 2024). One team has designed a kind of protein named ProAgio targeting integrinαvβ3, to specifically induce apoptosis of activated HSCs and LSECs, which consequently reduces collagen cross-linking, reverses hepatic sinusoidal remodeling as well as mitigates angiogenesis in fibrotic livers (Turaga et al., 2021). Interestingly, there are mechanobiological studies in which a novel perspective was given. During angiogenesis in the early stages of hepatic fibrosis, the mechanical tension generated by the contraction of LSECs was transmitted via collagen, which triggers the DDR2-JAK2/PI3K/AKT-cardiac muscle protein signaling pathway to initiate HSCs activation and ultimately augment the progression of hepatic fibrosis (Liu et al., 2017).

Lipids are deeply involved in the interaction between HSCs and LSECs. Adipocyte fatty acid binding protein (A-FABP), also called aP2 and FABP4, is an adipokine that is secreted into the microenvironment mainly by LSECs in liver fibrosis. In the BDL mouse model, the results of A-FABP knockdown experiments as well as overexpression experiments showed that A-FABP activates the Hh pathway and promotes capillarization of LSECs, as the expression of CD31, a biomarker of capillarization escalated. Meanwhile, A-FABP, in a paracrine manner, stimulates the JNK/c-Jun pathway in HSCs to promote activator protein-1 (AP-1) binding activity. AP-1 interacts with the AP-1 cis-acting sequence in the TGF-β1 promoter to stimulate the transactivation of TGF-β1 in HSCs, which further perpetuates the activation of HSCs (Wu et al., 2021). Since capillarization of LSECs matters in the fibrotic process in a variety of liver diseases, adding the circulating level of A-FABP is positively correlated with the degree of fibrosis in patients with NASH (Furuta et al., 2020), A-FABP is expected to serve as a potent target for inhibiting the fibrogenic pathological process of liver diseases (Wu et al., 2021).

Sphingosine-1-phosphate (S1P) participates in the physiological processes of inflammation, angiogenesis, and regulation of vascular permeability (Hisano and Hla, 2019). It has been exhibited that the sphingosine kinase/S1P/S1PR axis was involved in hepatic angiogenesis, the inhibition of which significantly decreases the mRNA levels of angiogenic markers (Ang1, CD31, VCAM-1) in vivo liver fibrosis (Yang et al., 2013). Like hepatocytes, LSECs are able to regulate HSCs activity through exosomes (Sung et al., 2018). LESCs can secrete exosomes within which phospho-sphingosine kinase 1 (SphK1), causes an increase of S1P in exosomes (Wang et al., 2015). S1P is involved in a wide range of cells involved in liver lesions, playing multiple roles in the hepatic microenvironment. TGF-β can mediate the upregulation of SphK1 in fibroblasts and thus elevate S1P levels (Yamanaka et al., 2004). It has been shown that after the internalization of exosomes by HSCs, S1P/SphK1 agonizes pAKT signaling and promotes HSCs activation. In contrast, the activating effects of exosome was attenuated after the use of S1PR2 receptor inhibitors (Barrow et al., 2023). Salidroside (Sal), a phenolic compound presented in the Rhodiola rosea plant, has been reported to have efficacy in a wide range of liver fibrosis. Sal inhibits the expression of SphK1 in serum exosomes as well as HSCs migration induced. In reports where LSECs secreted high levels of SphK1 in exosomes in CCl4-induced hepatic fibrosis, facts were demonstrated that Sal was able to hamper LX-2 activation by SphK1 in exosomes via blocking the activation of the AKT pathway (Ye et al., 2021). Moreover, there are reports that inhibition and silencing of SphK1 can inhibit HSCs activation. In a SphK1 knockout mouse model, less CCL2 is secreted by macrophages and miR-19b-3p is upregulated in HSCs, leading to a corresponding decrease of CCR2 in HSCs membranes by targeting CCR2 (Lan et al., 2018). Similarly, in a mouse model of ischemia-reperfusion in the liver in vitro, exosomes deliver SK2 to hepatocytes, resulting in intracellular production of S1P and promoting cell proliferation. However, exosomes from KCs and LSECs lack the same pro-proliferative effect (Nojima et al., 2016). Conversely, S1PR2 on LSECs was able to stimulate TGF-β expression via the YAP pathway, and HSCs were activated by paracrine TGF-β (Liao et al., 2023).

5.2 Fibroblast subpopulations

There are different HSCs subgroups in the liver. With gene expression and spatial heterogeneity, they interact and cooperate with each other in generating hepatic ECM. Among the genes specifically expressed by HSCs, the expression of Glypican-3 (GPC3) and DBH genes are mutually exclusive. According to the expression of different specific genes, HSCs are divided into two main subgroups, one is HSC1 (GPC3+), which is mainly confined to the area of the portal vein and central vein, expressing genes such as Neurotrophic Tyrosine Kinase, Receptor, Type 2(NTRK2). The other is HSC2 (DBH+), which is diffusely distributed around the hepatic sinusoids and mainly expresses genes responsible for antigen presentation. However, the presence of a GPC3-DBH- subpopulation of HSCs should also be noted (Payen et al., 2021). Depending on the selection of marker genes, HSCs can also be divided into different subgroups. In other studies, HSCs have been identified into three subgroups (Fred et al., 2022). For example, using Ngfe and Adamtsl2 genes, HSCs are divided into central vein-associated HSCs (CaHSCs) and portal vein-associated HSCs (PaHSCs), which are considered to be the main HSCs producing ECM under CCl4-induced hepatotoxicity and cholestatic liver injury, respectively (Xiong et al., 2019; Dobie et al., 2019; Rosenthal et al., 2021). The spatially specific distribution of HSCs subgroups has reached a consensus, despite the differences in the genes used to categorize them. In the context of liver disease, different subpopulations of HSCs show different activity characteristics as the disease progresses, allowing for the analysis of additional subpopulations such as proliferative (pHSCs), inflammatory (iHSCs), intermediate activation/vascular (vHSCs), contractile/migratory (cmHSCs), and fibrotic myofibroblasts (myHSCs) (Xiong et al., 2019; Rosenthal et al., 2021; Yang et al., 2021; Zhang W. et al., 2021; Krenkel et al., 2019) (Table 1). Yet, there is no universal subpopulation classification with specificity. In addition, lysophosphatidic acid receptor 1 (LPAR1) has been identified as a therapeutic target in collagen-producing HSCs (Dobie et al., 2019).

Table 1

Table 1. The heterogeneity of HSCs with the different characters and functions.

In liver fibrosis, different parts of the liver have different characteristics during the pathologic process due to the spatially differential distribution of different HSCs subpopulations. For example, in the course of liver fibrosis, the phenomenon of uneven distribution of stiff regions of the liver, called stiffness heterogeneity (Kostallari et al., 2022). In the Adamtsl2+ HSCs subpopulation responsible for stiffness heterogeneity, focal adhesion genes (including FHL2) are particularly upregulated due to increased stiffness, promoting HSCs activation (Kostallari et al., 2022). A team labeled HSCs in the periportal region of the hepatic lobule as zone 1 HSCs using SMMHC-CreERT2. In the liver fibrosis model, zone 1 HSCs did not transform into α-SMA-expressing myofibroblasts but were involved in the capillarization of LSECs, suggesting that HSCs subpopulations distributed in different regions are involved in different physiological and biochemical responses (Khan et al., 2024). One study analyzed the HSCs’ secretome genes and found that HSCs can secrete “stellakines” to function as an autocrine/paracrine traffic hub. At the same time, HSCs express a large number of membrane receptors, and several vasoactive hormones interact with G-coupled receptors on the HSCs cell membrane to regulate HSCs contraction (Xiong et al., 2019).

In HCC, the heterogeneity of HSCs has received a lot of attention. Cancer-associated fibroblast (CAF), mainly derived from HSCs, is the most abundant and critical component of the tumor microenvironment (TME), capable of regulating dynamic and complex pathways. CAFs have different subpopulations, ECM remodeling/myofibroblast CAF, pro-inflammatory CAF, immune-regulatory CAF, and antigen-presenting CAF (Lavie et al., 2022). Through ligand-receptor interactions, release of growth factors and inflammatory cytokines, and deposition of ECM components, CAFs are able to directly stimulate cancer cell proliferation or indirectly contribute to tumor development by promoting angiogenesis and remodeling of the microenvironment. iHSCs subpopulation in intrahepatic cholangiocarcinoma (iCCA) secretes HGF, which promotes tumor growth, while in another model of iCCA, myofibroblast CAF subpopulation can secrete type I collagen, which contributes to tumor stiffness without affecting tumor growth; however, myCAF also secretes hyaluronidase 2 (HA2), which promotes the growth and development of iCCA without affecting the stiffness of ECM (Affo et al., 2021). Similarly, studies have focused on cyHSCs, which are enriched with cytokines and growth factors such as the HGF pathway, and HSCs, which are enriched with type I collagen-rich myofibroblasts, in hepatocellular fibrosis. cyHSCs are negatively correlated with myHSCs, with a decrease in cyHSCs and a corresponding increase in myHSCs. myHSCs promote HCC progression, whereas cyHSCs are able to secrete HGF to inhibit tumorigenesis. The balance between cyHSCs and myHSCs during the pathological process influences hepatocellular carcinogenesis (Filliol et al., 2022) (Table 1).

Corresponding to HSCs heterogeneity, the scRNA-seq technique likewise revealed the heterogeneity of hepatocytes, intrahepatic macrophages as well as cholangiocytes (Andrews et al., 2022), giving a more promising outlook for the study of liver diseases (Cheng et al., 2020). Although the heterogeneity of various cells in different pathological conditions of the liver has been studied intensively, the crosstalk within subpopulations and between each subpopulation and other cells still needs to be further explored.

6 Conclusions and future perspectives

Current understanding suggests that liver fibrosis and early cirrhosis may be reversible. Therefore, the study of liver fibrosis has emerged as a prominent topic within the field of liver disease. Considering the liver is a complex organ containing various cell types, including hepatocytes, LSECs, hepatic macrophages, HSCs, and other immune cells, the interactions among various cell types must be taken seriously when exploring the influence and mechanisms underlying liver fibrosis. While on this basis, the primary cells responsible for triggering liver fibrosis may vary when specific factors inducing liver injury, leading to different responses mediated by associated genes. Therefore, different targeted treatment and prevention strategies should be adopted for the primary cells that cause liver fibrosis due to different reasons, and the time-dependent therapeutic strategies depended on the primary cells responsible for triggering liver fibrosis should also be considered.

Author contributions

LW: Data curation, Conceptualization, Writing – original draft, Visualization. YH: Writing – original draft, Visualization, Data curation, Conceptualization. JC: Writing – original draft, Methodology, Visualization. JG: Methodology, Conceptualization, Writing – original draft. SC: Methodology, Visualization, Writing – original draft. MZ: Writing – review and editing. JL: Writing – review and editing. SZ: Writing – review and editing. YS: Writing – review and editing, Supervision, Conceptualization. YC: Writing – review and editing, Supervision, Conceptualization, Funding acquisition.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by the National Natural Science Foundation of China (82304082) and the 8th young science and technology talents lift project of Jilin Province (QT202426), Science and Technology Development Program of Jilin Province (YDZJ202401199ZYTS), the Bethune Project of Jilin University (2024B39).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

Affo, S., Nair, A., Brundu, F., Ravichandra, A., Bhattacharjee, S., Matsuda, M., et al. (2021). Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39 (6), 866–882.e11. doi:10.1016/j.ccell.2021.03.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Allen, K., Kim, N. D., Moon, J. O., and Copple, B. L. (2010). Upregulation of early growth response factor-1 by bile acids requires mitogen-activated protein kinase signaling. Toxicol. Appl. Pharmacol. 243 (1), 63–67. doi:10.1016/j.taap.2009.11.013

PubMed Abstract | CrossRef Full Text | Google Scholar

An, P., Wei, L. L., Zhao, S., Sverdlov, D. Y., Vaid, K. A., Miyamoto, M., et al. (2020). Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nat. Commun. 11 (1), 2362. doi:10.1038/s41467-020-16092-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Andrews, T. S., Atif, J., Liu, J. C., Perciani, C. T., Ma, X. Z., Thoeni, C., et al. (2022). Single-cell, single-nucleus, and spatial RNA sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity. Hepatol. Commun. 6 (4), 821–840. doi:10.1002/hep4.1854

PubMed Abstract | CrossRef Full Text | Google Scholar

Annunziato, F., Cosmi, L., Santarlasci, V., Maggi, L., Liotta, F., Mazzinghi, B., et al. (2007). Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861. doi:10.1084/jem.20070663

PubMed Abstract | CrossRef Full Text | Google Scholar

Arias, J., Yu, J., Varshney, M., Inzunza, J., and Nalvarte, I. (2021). Hematopoietic stem cell- and induced pluripotent stem cell-derived CAR-NK cells as reliable cell-based therapy solutions. Stem Cells Transl. Med. 10 (7), 987–995. doi:10.1002/sctm.20-0459

PubMed Abstract | CrossRef Full Text | Google Scholar

Aseem, S. O., Jalan-Sakrikar, N., Chi, C., Navarro-Corcuera, A., De Assuncao, T. M., Hamdan, F. H., et al. (2021). Epigenomic evaluation of cholangiocyte transforming growth Factor-β signaling identifies a selective role for histone 3 lysine 9 acetylation in biliary fibrosis. Gastroenterology 160 (3), 889–905.e10. doi:10.1053/j.gastro.2020.10.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Austin, R. L., Rune, A., Bouzakri, K., Zierath, J. R., and Krook, A. (2008). siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle. Diabetes 57, 2066–2073. doi:10.2337/db07-0763

PubMed Abstract | CrossRef Full Text | Google Scholar

Baeck, C., Wei, X., Bartneck, M., Fech, V., Heymann, F., Gassler, N., et al. (2014). Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (Monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C+ macrophage infiltration in mice. Hepatology 59, 1060–1072. doi:10.1002/hep.26783

PubMed Abstract | CrossRef Full Text | Google Scholar

Ballak, D. B., Li, S., Cavalli, G., Stahl, J. L., Tengesdal, I. W., van Diepen, J. A., et al. (2018). Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue. J. Biol. Chem. 293, 14224–14236. doi:10.1074/jbc.RA118.003698

PubMed Abstract | CrossRef Full Text | Google Scholar

Barrow, F., Khan, S., Fredrickson, G., Wang, H., Dietsche, K., Parthiban, P., et al. (2021). Microbiota-driven activation of intrahepatic B cells aggravates NASH through innate and adaptive signaling. Hepatology 74 (2), 704–722. doi:10.1002/hep.31755

PubMed Abstract | CrossRef Full Text | Google Scholar

Barrow, F., Wang, H., Fredrickson, G., Florczak, K., Ciske, E., Khanal, S., et al. (2023). Pyruvate oxidation sustains B cell antigen-specific activation to exacerbate MASH. bioRxiv Prepr. 2023.11.13.566832. doi:10.1101/2023.11.13.566832

PubMed Abstract | CrossRef Full Text | Google Scholar

Barthel, A., Schmoll, D., and Unterman, T. G. (2005). FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16 (4), 183–189. doi:10.1016/j.tem.2005.03.010

PubMed Abstract | CrossRef Full Text | Google Scholar

Birkenfeld, A. L., and Shulman, G. I. (2014). Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 59 (2), 713–723. doi:10.1002/hep.26672

PubMed Abstract | CrossRef Full Text | Google Scholar

Bojic, L. A., and Huff, M. W. (2013). Peroxisome proliferator-activated receptor δ: a multifaceted metabolic player. Curr. Opin. Lipidol. 24, 171–177. doi:10.1097/MOL.0b013e32835cc949

PubMed Abstract | CrossRef Full Text | Google Scholar

Bonnardel, J., T'Jonck, W., Gaublomme, D., Browaeys, R., Scott, C. L., Martens, L., et al. (2019). Stellate cells, hepatocytes, and endothelial cells imprint the kupffer cell identity on monocytes colonizing the liver macrophage niche. Immunity 51 (4), 638–654.e9. doi:10.1016/j.immuni.2019.08.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Böttcher, K., Rombouts, K., Saffioti, F., Roccarina, D., Rosselli, M., Hall, A., et al. (2018). MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation. Hepatology 68 (1), 172–186. doi:10.1002/hep.29782

PubMed Abstract | CrossRef Full Text | Google Scholar

Boyer-Diaz, Z., Aristu-Zabalza, P., Andres-Rozas, M., Robert, C., Ortega-Ribera, M., Fernandez-Iglesias, A., et al. (2020). Pan-PPAR agonist lanifibranor improves portal hypertension and hepatic fibrosis in experimental advanced chronic liver disease. J. Hepatol. 74, 1188–1199. doi:10.1016/j.jhep.2020.11.045

PubMed Abstract | CrossRef Full Text | Google Scholar

Britton, L., Bridle, K., Reiling, J., Santrampurwala, N., Wockner, L., Ching, H., et al. (2018). Hepatic iron concentration correlates with insulin sensitivity in nonalcoholic fatty liver disease. Hepatol. Commun. 2 (6), 644–653. doi:10.1002/hep4.1190

PubMed Abstract | CrossRef Full Text | Google Scholar

Cai, S. Y., Ouyang, X., Chen, Y., Soroka, C. J., Wang, J., Mennone, A., et al. (2017). Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2 (5), e90780. doi:10.1172/jci.insight.90780

PubMed Abstract | CrossRef Full Text | Google Scholar

Cai, X., Li, Z., Zhang, Q., Qu, Y., Xu, M., Wan, X., et al. (2018). CXCL6-EGFR-induced kupffer cells secrete TGF-β1 promoting hepatic stellate cell activation via the SMAD2/BRD4/C-MYC/EZH2 pathway in liver fibrosis. J. Cell. Mol. Med. 22, 5050–5061. doi:10.1111/jcmm.13787

PubMed Abstract | CrossRef Full Text | Google Scholar

Cardoso, C. C., Matiollo, C., Pereira, C. H. J., Fonseca, J. S., Alves, H. E. L., Silva, O. M. D., et al. (2021). B-cell compartment abnormalities are associated with ACLF and mortality in patients with liver cirrhosis. Clin. Res. Hepatol. Gastroenterol. 45 (4), 101698. doi:10.1016/j.clinre.2021.101698

PubMed Abstract | CrossRef Full Text | Google Scholar

Cargill, T., and Culver, E. L. (2021). The role of B cells and B cell therapies in immune-mediated liver diseases. Front. Immunol. 12, 661196. doi:10.3389/fimmu.2021.661196

PubMed Abstract | CrossRef Full Text | Google Scholar

Chan, M. M., He, L., Finck, B. N., Schilling, J. D., and Daemen, S. (2024). Cutting edge: hepatic stellate cells drive the phenotype of monocyte-Derived macrophages to regulate liver fibrosis in metabolic dysfunction-associated steatohepatitis. J. Immunol. 213 (3), 251–256. doi:10.4049/jimmunol.2300847

PubMed Abstract | CrossRef Full Text | Google Scholar

Chang, J., Hisamatsu, T., Shimamura, K., Yoneno, K., Adachi, M., Naruse, H., et al. (2013). Activated hepatic stellate cells mediate the differentiation of macrophages. Hepatol. Res. 43 (06), 658–669. doi:10.1111/j.1872-034X.2012.01111.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Charles, R., Chou, H. S., Wang, L., Fung, J. J., Lu, L., and Qian, S. (2013). Human hepatic stellate cells inhibit T-cell response through B7-H1 pathway. Transplantation 96, 17–24. doi:10.1097/TP.0b013e318294caae

PubMed Abstract | CrossRef Full Text | Google Scholar

Chazaud, B. (2014). Macrophages: supportive cells for tissue repair and regeneration. Immunobiology 219, 172–178. doi:10.1016/j.imbio.2013.09.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, L., Gu, T., Li, B., Li, F., Ma, Z., Zhang, Q., et al. (2019). Delta-like ligand 4/DLL4 regulates the capillarization of liver sinusoidal endothelial cell and liver fibrogenesis. Biochim. Biophys. Acta Mol. Cell Res. 1866 (10), 1663–1675. doi:10.1016/j.bbamcr.2019.06.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, L., Zhou, T., White, T., O'Brien, A., Chakraborty, S., Liangpunsakul, S., et al. (2021). The apelin-apelin receptor axis triggers cholangiocyte proliferation and liver fibrosis during mouse models of cholestasis. Hepatology 73 (6), 2411–2428. doi:10.1002/hep.31545

PubMed Abstract | CrossRef Full Text | Google Scholar

Chen, T., Shi, Z., Zhao, Y., Meng, X., Zhao, S., Zheng, L., et al. (2022). LncRNA airn maintains LSEC differentiation to alleviate liver fibrosis via the KLF2-eNOS-sGC pathway. BMC Med. 20 (1), 335. doi:10.1186/s12916-022-02523-w

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheng, N., Kim, K. H., and Lau, L. F. (2022). Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2. JCI Insight 7 (14), e158207. doi:10.1172/jci.insight.158207

PubMed Abstract | CrossRef Full Text | Google Scholar

Cheng, S., Zou, Y., Zhang, M., Bai, S., Tao, K., Wu, J., et al. (2020)2023). Single-cell RNA sequencing reveals the heterogeneity and intercellular communication of hepatic stellate cells and macrophages during liver fibrosis. MedComm 4 (5), e378. doi:10.1002/mco2.378

PubMed Abstract | CrossRef Full Text | Google Scholar

Choudhary, N. S., Kumar, N., and Duseja, A. (2019). Peroxisome proliferator-activated receptors and their agonists in nonalcoholic fatty liver disease. J. Clin. Exp. Hepatol. 9, 731–739. doi:10.1016/j.jceh.2019.06.004

PubMed Abstract | CrossRef Full Text | Google Scholar

Daemen, S., Gainullina, A., Kalugotla, G., He, L., Chan, M. M., Beals, J. W., et al. (2021). Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH. Cell Rep. 34, 108626. doi:10.1016/j.celrep.2020.108626

PubMed Abstract | CrossRef Full Text | Google Scholar

Dai, H., Zhu, C., Huai, Q., Xu, W., Zhu, J., Zhang, X., et al. (2024). Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models. J. Hepatol. 80 (6), 913–927. doi:10.1016/j.jhep.2024.01.034

PubMed Abstract | CrossRef Full Text | Google Scholar

Dal-Secco, D., Wang, J., Zeng, Z., Kolaczkowska, E., Wong, C. H. Y., Petri, B., et al. (2015). A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of Sterile injury. J. Exp. Med. 212, 447–456. doi:10.1084/jem.20141539

PubMed Abstract | CrossRef Full Text | Google Scholar

de Haan, W., Dheedene, W., Apelt, K., Décombas-Deschamps, S., Vinckier, S., Verhulst, S., et al. (2022). Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis. Cardiovasc Res. 118 (5), 1262–1275. doi:10.1093/cvr/cvab148

PubMed Abstract | CrossRef Full Text | Google Scholar

DeLeve, L. D. (2015). Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61 (5), 1740–1746. doi:10.1002/hep.27376

PubMed Abstract | CrossRef Full Text | Google Scholar

Ding, B. S., Cao, Z., Lis, R., Nolan, D. J., Guo, P., Simons, M., et al. (2014). Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505 (7481), 97–102. doi:10.1038/nature12681

PubMed Abstract | CrossRef Full Text | Google Scholar

Dobie, R., Wilson-Kanamori, J. R., Henderson, B. E. P., Smith, J. R., Matchett, K. P., Portman, J. R., et al. (2019). Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep. 29 (7), 1832–1847. doi:10.1016/j.celrep.2019.10.024

PubMed Abstract | CrossRef Full Text | Google Scholar

Dou, J. Y., Zhou, M. J., Xuan, M. Y., Guo, J., Liu, S. H., Lian, L. H., et al. (2024). Astilbin alleviates hepatic fibrosis through PXR-PINK1/Parkin pathway: a new strategy by regulating hepatic stellate cells-macrophage crosstalk. Phytomedicine 135, 156144. doi:10.1016/j.phymed.2024.156144

PubMed Abstract | CrossRef Full Text | Google Scholar

Du, P., Ma, Q., Zhu, Z. D., Li, G., Wang, Y., Li, Q. Q., et al. (2016). Mechanism of corilagin interference with IL-13/STAT6 signaling pathways in hepatic alternative activation macrophages in schistosomiasis-induced liver fibrosis in mouse model. Eur. J. Pharmacol. 793, 119–126. doi:10.1016/j.ejphar.2016.11.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Duan, J. L., Ruan, B., Yan, X. C., Liang, L., Song, P., Yang, Z. Y., et al. (2018). Endothelial notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice. Hepatology 68 (2), 677–690. doi:10.1002/hep.29834

PubMed Abstract | CrossRef Full Text | Google Scholar

Dudek, M., Pfister, D., Donakonda, S., Filpe, P., Schneider, A., Laschinger, M., et al. (2021). Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 592 (7854), 444–449. doi:10.1038/s41586-021-03233-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Duffield, J. S., Forbes, S. J., Constandinou, C. M., Clay, S., Partolina, M., Vuthoori, S., et al. (2005). Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest 115 (01), 56–65. doi:10.1172/JCI22675

PubMed Abstract | CrossRef Full Text | Google Scholar

Dunham, R. M., Thapa, M., Velazquez, V. M., Elrod, E. J., Denning, T. L., Pulendran, B., et al. (2013). Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. J. Immunol. 190, 2009–2016. doi:10.4049/jimmunol.1201937

PubMed Abstract | CrossRef Full Text | Google Scholar

Faggioli, F., Palagano, E., Di Tommaso, L., Donadon, M., Marrella, V., Recordati, C., et al. (2018). B lymphocytes limit senescence-driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury. Hepatology 67, 1970–1985. doi:10.1002/hep.29636

PubMed Abstract | CrossRef Full Text | Google Scholar

Fan, J. H., Luo, N., Liu, G. F., Xu, X. F., Li, S. Q., and Lv, X. P. (2023). Mechanism of annexin A1/N-formylpeptide receptor regulation of macrophage function to inhibit hepatic stellate cell activation through Wnt/β-catenin pathway. World J. Gastroenterol. 29 (22), 3422–3439. doi:10.3748/wjg.v29.i22.3422

PubMed Abstract | CrossRef Full Text | Google Scholar

Feng, X., Feng, B., Zhou, J., Yang, J., Pan, Q., Yu, J., et al. (2025). Mesenchymal stem cells alleviate mouse liver fibrosis by inhibiting pathogenic function of intrahepatic B cells. Hepatology 81 (4), 1211–1227. doi:10.1097/HEP.0000000000000831

PubMed Abstract | CrossRef Full Text | Google Scholar

Fernandez-Ruiz, D., Ng, W. Y., Holz, L. E., Ma, J. Z., Zaid, A., Wong, Y. C., et al. (2016). Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection. Immunity 45, 889–902. doi:10.1016/j.immuni.2016.08.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Filliol, A., Saito, Y., Nair, A., Dapito, D. H., Yu, L. X., Ravichandra, A., et al. (2022). Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610 (7931), 356–365. doi:10.1038/s41586-022-05289-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Francis, H., McDaniel, K., Han, Y., Liu, X., Kennedy, L., Yang, F., et al. (2014). Regulation of the extrinsic apoptotic pathway by microRNA-21 in alcoholic liver injury. J. Biol. Chem. 289 (40), 27526–27539. doi:10.1074/jbc.M114.602383

PubMed Abstract | CrossRef Full Text | Google Scholar

Francque, S., Verrijken, A., Caron, S., Prawitt, J., Paumelle, R., Derudas, B., et al. (2015). PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J. Hepatol. 63, 164–173. doi:10.1016/j.jhep.2015.02.019

PubMed Abstract | CrossRef Full Text | Google Scholar

Francque, S. M., Bedossa, P., Ratziu, V., Anstee, Q. M., Bugianesi, E., Sanyal, A. J., et al. (2021). A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385, 1547–1558. doi:10.1056/NEJMoa2036205

PubMed Abstract | CrossRef Full Text | Google Scholar

Fred, R. G., Steen Pedersen, J., Thompson, J. J., Lee, J., Timshel, P. N., Stender, S., et al. (2022). Single-cell transcriptome and cell type-specific molecular pathways of human non-alcoholic steatohepatitis. Sci. Rep. 12 (1), 13484. doi:10.1038/s41598-022-16754-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Fu, B., Tian, Z., and Wei, H. (2014). Subsets of human natural killer cells and their regulatory effects. Immunology 141, 483–489. doi:10.1111/imm.12224

PubMed Abstract | CrossRef Full Text | Google Scholar

Fu, B., Wang, F., Sun, R., Ling, B., Tian, Z., and Wei, H. (2011). CD11b and CD27 reflect distinct population and functional specialization in human natural killer cells. Immunology 133, 350–359. doi:10.1111/j.1365-2567.2011.03446.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Furuta, K., Guo, Q., Hirsova, P., and Ibrahim, S. H. (2020). Emerging roles of liver sinusoidal endothelial cells in nonalcoholic steatohepatitis. Biol. (Basel). 9 (11), 395. doi:10.3390/biology9110395

PubMed Abstract | CrossRef Full Text | Google Scholar

Gao, H., Jin, Z., Bandyopadhyay, G., Wang, G., Zhang, D., Rocha, K. C. E., et al. (2022). Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis. Cell Metab. 34 (8), 1201–1213.e5. doi:10.1016/j.cmet.2022.07.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Garcia-Martinez, I., Santoro, N., Chen, Y., Hoque, R., Ouyang, X., Caprio, S., et al. (2016). Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J. Clin. Invest 126 (3), 859–864. doi:10.1172/JCI83885

PubMed Abstract | CrossRef Full Text | Google Scholar

Glässner, A., Eisenhardt, M., Krämer, B., Körner, C., Coenen, M., Sauerbruch, T., et al. (2012). NK cells from HCV-Infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-FasL- and NKG2D-dependent manner. Lab. Invest 92 (7), 967–977. doi:10.1038/labinvest.2012.54

PubMed Abstract | CrossRef Full Text | Google Scholar

Gou, Y., Wang, H., Wang, T., Wang, H., Wang, B., Jiao, N., et al. (2023). Ectopic endometriotic stromal cells-derived lactate induces M2 macrophage polarization via Mettl3/Trib1/ERK/STAT3 signalling pathway in endometriosis. Immunology 168 (3), 389–402. doi:10.1111/imm.13574

PubMed Abstract | CrossRef Full Text | Google Scholar

Haaker, M. W., Chang, J. C., Chung, B. K., Pieper, T. S., Noé, F., Wang, T., et al. (2025). Cellular crosstalk promotes hepatic progenitor cell proliferation and stellate cell activation in 3D Co-culture. Cell Mol. Gastroenterol. Hepatol. 19 (5), 101472. doi:10.1016/j.jcmgh.2025.101472

PubMed Abstract | CrossRef Full Text | Google Scholar

Hammerich, L., Bangen, J. M., Govaere, O., Zimmermann, H. W., Gassler, N., Huss, S., et al. (2014). Chemokine receptor CCR6-dependent accumulation of γδ T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology 59, 630–642. doi:10.1002/hep.26697

PubMed Abstract | CrossRef Full Text | Google Scholar

Hammerich, L., and Tacke, F. (2023). Hepatic inflammatory responses in liver fibrosis. Nat. Rev. Gastroenterol. Hepatol. 20 (10), 633–646. doi:10.1038/s41575-023-00807-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Han, C., Sheng, Y., Wang, J., Zhou, X., Li, W., Guo, L., et al. (2023). TFAP4 promotes the progression of liver fibrosis through regulating double-negative T cell differentiation via OX40. Int. Immunopharmacol. 119, 110164. doi:10.1016/j.intimp.2023.110164

PubMed Abstract | CrossRef Full Text | Google Scholar

He, S., Luo, Y., Ma, W., Wang, X., Yan, C., Hao, W., et al. (2024). Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis. J. Hepatol. 81 (1), 135–148. doi:10.1016/j.jhep.2024.02.032

PubMed Abstract | CrossRef Full Text | Google Scholar

Hellemans, K., Michalik, L., Dittie, A., Knorr, A., Rombouts, K., De Jong, J., et al. (2003). Peroxisome proliferator-activated receptor-beta signaling contributes to enhanced proliferation of hepatic stellate cells. Gastroenterology 124, 184–201. doi:10.1053/gast.2003.50015

PubMed Abstract | CrossRef Full Text | Google Scholar

Hisano, Y., and Hla, T. (2019). Bioactive lysolipids in cancer and angiogenesis. Pharmacol. Ther. 193, 91–98. doi:10.1016/j.pharmthera.2018.07.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Hoogeveen, R. C., Robidoux, M. P., Schwarz, T., Heydmann, L., Cheney, J. A., Kvistad, D., et al. (2019). Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. Gut 68, 893–904. doi:10.1136/gutjnl-2018-316644

PubMed Abstract | CrossRef Full Text | Google Scholar

Huang, S., Chen, L., Lu, L., and Li, L. (2016). The apelin-APJ axis: a novel potential therapeutic target for organ fibrosis. Clin. Chim. Acta 456, 81–88. doi:10.1016/j.cca.2016.02.025

PubMed Abstract | CrossRef Full Text | Google Scholar

Huang, Y., Luo, W., Yang, Z., Lan, T., Wei, X., and Wu, H. (2024). Machine learning and experimental validation identified autophagy signature in hepatic fibrosis. Front. Immunol. 15, 1337105. doi:10.3389/fimmu.2024.1337105

PubMed Abstract | CrossRef Full Text | Google Scholar

Ishizuka, K., Usui, I., Kanatani, Y., Bukhari, A., He, J., Fujisaka, S., et al. (2007). Chronic tumor necrosis factor-alpha treatment causes insulin resistance via insulin receptor substrate-1 serine phosphorylation and suppressor of cytokine signaling-3 induction in 3T3-L1 adipocytes. Endocrinology 148, 2994–3003. doi:10.1210/en.2006-1702

PubMed Abstract | CrossRef Full Text | Google Scholar

Islam, D., Israr, I., Taleb, M. A. B., Rao, A., Yosief, R., Sultana, R., et al. (2024). A novel model to study mechanisms of cholestasis in human cholangiocytes reveals a role for the SIPR2 pathway. Hepatol. Commun. 8 (3), e0389. doi:10.1097/HC9.0000000000000389

PubMed Abstract | CrossRef Full Text | Google Scholar

Isogawa, M., and Tanaka, Y. (2015). Immunobiology of hepatitis B virus infection. Hepatol. Res. 45, 179–189. doi:10.1111/hepr.12439

PubMed Abstract | CrossRef Full Text | Google Scholar

Jalan-Sakrikar, N., De Assuncao, T. M., Shi, G., Aseem, S. O., Chi, C., Shah, V. H., et al. (2019). Proteasomal degradation of enhancer of zeste homologue 2 in cholangiocytes promotes biliary fibrosis. Hepatology 70 (5), 1674–1689. doi:10.1002/hep.30706

PubMed Abstract | CrossRef Full Text | Google Scholar

Jani, M., Beéry, E., Heslop, T., Tóth, B., Jagota, B., Kis, E., et al. (2018). Kinetic characterization of bile salt transport by human NTCP (SLC10A1). Toxicol Vitro 46, 189–193. doi:10.1016/j.tiv.2017.10.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Jiang, S., Lu, J., Li, N., Bai, X., Shi, L., Tian, Z., et al. (2025). Liver B cells promotes MASLD progression via the Apelin/APLNR system. Int. J. Med. Sci. 22 (1), 197–208. doi:10.7150/ijms.101492

PubMed Abstract | CrossRef Full Text | Google Scholar

Jiang, X., Peng, Y., Liu, L., Wang, Y., Li, M., Li, W., et al. (2022). MAIT cells ameliorate liver fibrosis by enhancing the cytotoxicity of NK cells in cholestatic murine models. Liver Int. 42 (12), 2743–2758. doi:10.1111/liv.15445

PubMed Abstract | CrossRef Full Text | Google Scholar

Jiang, Y., Hou, L., Dou, J., Xuan, M., Cui, Z., Lian, L., et al. (2024). Sesamol as a potential candidate for the treatment of hepatic fibrosis, based on its regulation of FXR/LXR axis-mediated inhibition of autophagy through crosstalk between hepatic cells and macrophage. Phytomedicine 123, 155145. doi:10.1016/j.phymed.2023.155145

PubMed Abstract | CrossRef Full Text | Google Scholar

Jones, H., Hargrove, L., Kennedy, L., Meng, F., Graf-Eaton, A., Owens, J., et al. (2016). Inhibition of mast cell-secreted histamine decreases biliary proliferation and fibrosis in primary sclerosing cholangitis Mdr2(-/-) mice. Hepatology 64 (4), 1202–1216. doi:10.1002/hep.28704

PubMed Abstract | CrossRef Full Text | Google Scholar

Kennedy, L. L., Meng, F., Venter, J. K., Zhou, T., Karstens, W. A., Hargrove, L. A., et al. (2016). Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice. Lab. Invest 96 (12), 1256–1267. doi:10.1038/labinvest.2016.112

PubMed Abstract | CrossRef Full Text | Google Scholar

Khan, M. A., Fischer, J., Harrer, L., Schwiering, F., Groneberg, D., and Friebe, A. (2024). Hepatic stellate cells in zone 1 engage in capillarization rather than myofibroblast formation in murine liver fibrosis. Sci. Rep. 14 (1), 18840. doi:10.1038/s41598-024-69898-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Kim, K. H., Chen, C. C., Alpini, G., and Lau, L. F. (2015). CCN1 induces hepatic ductular reaction through integrin αvβ₅-mediated activation of NF-κB. J. Clin. Invest 125 (5), 1886–1900. doi:10.1172/JCI79327

PubMed Abstract | CrossRef Full Text | Google Scholar

Kim, K. H., Chen, C. C., Monzon, R. I., and Lau, L. F. (2013). Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol. Cell Biol. 33 (10), 2078–2090. doi:10.1128/MCB.00049-13

PubMed Abstract | CrossRef Full Text | Google Scholar

Kisseleva, T., and Brenner, D. (2021). Molecular and cellular mechanisms of liver fibrosis and its regression. Nat. Rev. Gastroenterol. Hepatol. 18, 151–166. doi:10.1038/s41575-020-00372-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Koda, Y., Teratani, T., Chu, P. S., Hagihara, Y., Mikami, Y., Harada, Y., et al. (2021). CD8⁺ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nat. Commun. 12(1):4474. doi:10.1038/s41467-021-24734-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Kojima, H., Sakurai, S., Kuriyama, S., Yoshiji, H., Imazu, H., Uemura, M., et al. (2001). Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B together with subtype A in vivo. J. Hepatol. 34 (6), 805–811. doi:10.1016/s0168-8278(01)00045-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Kostallari, E., Wei, B., Sicard, D., Li, J., Cooper, S. A., Gao, J., et al. (2022). Stiffness is associated with hepatic stellate cell heterogeneity during liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 322 (2), G234–G246. doi:10.1152/ajpgi.00254.2021

PubMed Abstract | CrossRef Full Text | Google Scholar

Krenkel, O., Hundertmark, J., Ritz, T. P., Weiskirchen, R., and Tacke, F. (2019). Single cell RNA sequencing identifies subsets of hepatic stellate cells and myofibroblasts in liver fibrosis. Cells 8 (5), 503. doi:10.3390/cells8050503

PubMed Abstract | CrossRef Full Text | Google Scholar

Kruglov, E. A., Nathanson, R. A., Nguyen, T., and Dranoff, J. A. (2006). Secretion of MCP-1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. Am. J. Physiol. Gastrointest. Liver Physiol. 290 (4), G765–G771. doi:10.1152/ajpgi.00308.2005

PubMed Abstract | CrossRef Full Text | Google Scholar

Kumar, S., Wang, J., Thomson, A. W., and Gandhi, C. R. (2017). Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-Induced AhR activation. J. Leukoc. Biol. 101 (2), 429–438. doi:10.1189/jlb.2A0516-239R

PubMed Abstract | CrossRef Full Text | Google Scholar

Kuttkat, N., Mohs, A., Ohl, K., Hooiveld, G., Longerich, T., Tenbrock, K., et al. (2017). Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease. Gut 66 (5), 908–919. doi:10.1136/gutjnl-2015-311119

PubMed Abstract | CrossRef Full Text | Google Scholar

Lan, T., Li, C., Yang, G., Sun, Y., Zhuang, L., Ou, Y., et al. (2018). Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2. Hepatology 68 (3), 1070–1086. doi:10.1002/hep.29885

PubMed Abstract | CrossRef Full Text | Google Scholar

Langhans, B., Alwan, A. W., Krämer, B., Glässner, A., Lutz, P., Strassburg, C. P., et al. (2015). Regulatory CD4+ T cells modulate the interaction between NK cells and hepatic stellate cells by acting on either cell type. J. Hepatol. 62 (2), 398–404. doi:10.1016/j.jhep.2014.08.038

PubMed Abstract | CrossRef Full Text | Google Scholar

Lavie, D., Ben-Shmuel, A., Erez, N., and Scherz-Shouval, R. (2022). Cancer-associated fibroblasts in the single-cell era. Nat. Cancer 3 (7), 793–807. doi:10.1038/s43018-022-00411-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Lee, Y. S., Yi, H. S., Suh, Y. G., Byun, J. S., Eun, H. S., Kim, S. Y., et al. (2015). Blockade of retinol metabolism protects T cell-induced hepatitis by increasing migration of regulatory T cells. Mol. Cells 38 (11), 998–1006. doi:10.14348/molcells.2015.0218

PubMed Abstract | CrossRef Full Text | Google Scholar

Lefere, S., Puengel, T., Hundertmark, J., Penners, C., Frank, A. K., Guillot, A., et al. (2020). Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆. J. Hepatol. 73, 757–770. doi:10.1016/j.jhep.2020.04.025

PubMed Abstract | CrossRef Full Text | Google Scholar

Lei, Y., Xu, X., Liu, H., Chen, L., Zhou, H., Jiang, J., et al. (2021). HBx induces hepatocellular carcinogenesis through ARRB1-mediated autophagy to drive the G1/S cycle. Autophagy 17 (12), 4423–4441. doi:10.1080/15548627.2021.1917948

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, F., Huangyang, P., Burrows, M., Guo, K., Riscal, R., Godfrey, J., et al. (2020). FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat. Cell Biol. 22 (6), 728–739. doi:10.1038/s41556-020-0511-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, F., Yan, T., Wang, S., and Wen, X. (2023a). Exosome-associated miRNA-99a-5p targeting BMPR2 promotes hepatocyte apoptosis during the process of hepatic fibrosis. Clin. Exp. Med. 23 (7), 4021–4031. doi:10.1007/s10238-023-01122-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, H., and Xia, N. (2024). The multifaceted roles of B lymphocytes in metabolic dysfunction-associated steatotic liver disease. Front. Immunol. 15, 1447391. doi:10.3389/fimmu.2024.1447391

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, J., Zeng, C., Zheng, B., Liu, C., Tang, M., Jiang, Y., et al. (2018). HMGB1-induced autophagy facilitates hepatic stellate cells activation: a new pathway in liver fibrosis. Clin. Sci. (Lond). 132 (15), 1645–1667. doi:10.1042/CS20180177

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, M., Cai, S. Y., and Boyer, J. L. (2017). Mechanisms of bile acid mediated inflammation in the liver. Mol. Asp. Med. 56, 45–53. doi:10.1016/j.mam.2017.06.001

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, W., Yang, Y., Yang, L., Chang, N., and Li, L. (2023b). Monocyte-derived kupffer cells dominate in the kupffer cell pool during liver injury. Cell Rep. 42 (10), 113164. doi:10.1016/j.celrep.2023.113164

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, X., Su, Y., Hua, X., Xie, C., Liu, J., Huang, Y., et al. (2017). Levels of hepatic Th17 cells and regulatory T cells upregulated by hepatic stellate cells in advanced HBV-Related liver fibrosis. J. Transl. Med. 15 (1), 75. doi:10.1186/s12967-017-1167-y

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Kim, B. G., Qian, S., Letterio, J. J., Fung, J. J., Lu, L., et al. (2015). Hepatic stellate cells inhibit T cells through active TGF-β1 from a cell surface-bound latent TGF-β1/GARP complex. J. Immunol. 195 (6), 2648–2656. doi:10.4049/jimmunol.1500139

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Lu, L., Qian, S., Fung, J. J., and Lin, F. (2016). Hepatic stellate cells directly inhibit B cells via programmed death-ligand 1. J. Immunol. 196 (4), 1617–1625. doi:10.4049/jimmunol.1501737

PubMed Abstract | CrossRef Full Text | Google Scholar

Li, Y., Tu, Z., Qian, S., Fung, J. J., Markowitz, S. D., Kusner, L. L., et al. (2014). Myeloid-derived suppressor cells as a potential therapy for experimental autoimmune myasthenia gravis. J. Immunol. 193, 2127–2134. doi:10.4049/jimmunol.1400857

PubMed Abstract | CrossRef Full Text | Google Scholar

Liao, Y., Zhou, C., Duan, Y., Liu, X., Yue, J., Li, X., et al. (2023). Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF-β signaling pathway. FASEB J. 37 (5), e22905. doi:10.1096/fj.202201954R

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, B., Wang, J., Wang, G., Jiang, W., Li, Z., Shi, Y., et al. (2023b). Hepatocyte-derived exosomes deliver H2AFJ to hepatic stellate cells and promote liver fibrosis via the MAPK/STMN1 axis activation. Int. Immunopharmacol. 115, 109605. doi:10.1016/j.intimp.2022.109605

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, L., You, Z., Yu, H., Zhou, L., Zhao, H., Yan, X., et al. (2017). Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis. Nat. Mater 16 (12), 1252–1261. doi:10.1038/nmat5024

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, M., Hu, Y., Yuan, Y., Tian, Z., and Zhang, C. (2019b). γδT cells suppress liver fibrosis via strong cytolysis and enhanced NK cell-mediated cytotoxicity against hepatic stellate cells. Front. Immunol. 10, 477. doi:10.3389/fimmu.2019.00477

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, Q., Yang, Q., Wu, Z., Chen, Y., Xu, M., Zhang, H., et al. (2022). IL-1β-activated mTORC2 promotes accumulation of IFN-γ+ γδ T cells by upregulating CXCR3 to restrict hepatic fibrosis. Cell Death Dis. 13 (4), 289. doi:10.1038/s41419-022-04739-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, R., Li, X., Zhu, W., Wang, Y., Zhao, D., Wang, X., et al. (2019a). Cholangiocyte-derived exosomal long noncoding RNA H19 promotes hepatic stellate cell activation and cholestatic liver fibrosis. Hepatology 70 (4), 1317–1335. doi:10.1002/hep.30662

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, R., Zhao, R., Zhou, X., Liang, X., Campbell, D. J., Zhang, X., et al. (2014). Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2. Hepatology 60 (3), 908–918. doi:10.1002/hep.27085

PubMed Abstract | CrossRef Full Text | Google Scholar

Liu, X., Tan, S., Liu, H., Jiang, J., Wang, X., Li, L., et al. (2023a). Hepatocyte-derived MASP1-enriched small extracellular vesicles activate HSCs to promote liver fibrosis. Hepatology 77 (4), 1181–1197. doi:10.1002/hep.32662

PubMed Abstract | CrossRef Full Text | Google Scholar

Longhi, M. S., Zhang, L., Mieli-Vergani, G., and Vergani, D. (2024). B and T cells: (still) the dominant orchestrators in autoimmune hepatitis. Autoimmun. Rev. 23 (7-8), 103591. doi:10.1016/j.autrev.2024.103591

CrossRef Full Text | Google Scholar

Lu, H., Zhang, R., Zhang, S., Li, Y., Liu, Y., Xiong, Y., et al. (2023). HSC-Derived exosomal miR-199a-5p promotes HSC activation and hepatocyte EMT via targeting SIRT1 in hepatic fibrosis. Int. Immunopharmacol. 124 (Pt B), 111002. doi:10.1016/j.intimp.2023.111002

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, W., Xu, Q., Wang, Q., Wu, H., and Hua, J. (2017). Effect of modulation of PPAR-γ activity on kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci. Rep. 16, 44612. doi:10.1038/srep44612

PubMed Abstract | CrossRef Full Text | Google Scholar

Luo, X., Luo, S. Z., Xu, Z. X., Zhou, C., Li, Z. H., Zhou, X. Y., et al. (2021). Lipotoxic hepatocyte-derived exosomal miR-1297 promotes hepatic stellate cell activation through the PTEN signaling pathway in metabolic-associated fatty liver disease. World J. Gastroenterol. 27 (14), 1419–1434. doi:10.3748/wjg.v27.i14.1419

PubMed Abstract | CrossRef Full Text | Google Scholar

Lv, X., Kong, J., Chen, W. D., and Wang, Y. D. (2017). The role of the Apelin/APJ system in the regulation of liver disease. Front. Pharmacol. 8, 221. doi:10.3389/fphar.2017.00221

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, F., Liu, Y., Hu, Z., Xue, Y., Liu, Z., Cai, G., et al. (2023). Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression. Hepatology 78 (5), 1492–1505. doi:10.1097/HEP.0000000000000042

PubMed Abstract | CrossRef Full Text | Google Scholar

Ma, P. F., Gao, C. C., Yi, J., Zhao, J. L., Liang, S. Q., Zhao, Y., et al. (2017). Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice. J. Hepatol. 67 (4), 770–779. doi:10.1016/j.jhep.2017.05.022

PubMed Abstract | CrossRef Full Text | Google Scholar

Marrone, G., Maeso-Díaz, R., García-Cardena, G., Abraldes, J. G., García-Pagán, J. C., Bosch, J., et al. (2015). KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. Gut 64 (9), 1434–1443. doi:10.1136/gutjnl-2014-308338

PubMed Abstract | CrossRef Full Text | Google Scholar

Matsuda, M., Tsurusaki, S., Miyata, N., Saijou, E., Okochi, H., Miyajima, A., et al. (2018). Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice. Hepatology 67 (01), 296–312. doi:10.1002/hep.29421

PubMed Abstract | CrossRef Full Text | Google Scholar

Mazzoccoli, G., De Cosmo, S., and Mazza, T. (2018). The biological clock: a pivotal hub in non-alcoholic fatty liver disease pathogenesis. Front. Physiol. 9 (9), 193. doi:10.3389/fphys.2018.00193

PubMed Abstract | CrossRef Full Text | Google Scholar

Meadows, V., Kennedy, L., Hargrove, L., Demieville, J., Meng, F., Virani, S., et al. (2019). Downregulation of hepatic stem cell factor by vivo-morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2-/- mice. Biochim. Biophys. Acta Mol. Basis Dis. 1865 (12), 165557. doi:10.1016/j.bbadis.2019.165557

PubMed Abstract | CrossRef Full Text | Google Scholar

Mederacke, I., Filliol, A., Affo, S., Nair, A., Hernandez, C., Sun, Q., et al. (2022). The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver. Sci. Transl. Med. 14 (639), eabe5795. doi:10.1126/scitranslmed.abe5795

PubMed Abstract | CrossRef Full Text | Google Scholar

Meng, F., Kennedy, L., Hargrove, L., Demieville, J., Jones, H., Madeka, T., et al. (2018). Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2-/- mice and human primary sclerosing cholangitis. Lab. Invest 98 (11), 1465–1477. doi:10.1038/s41374-018-0101-0

PubMed Abstract | CrossRef Full Text | Google Scholar

Mikulak, J., Bruni, E., Oriolo, F., Di Vito, C., and Mavilio, D. (2019). Hepatic natural killer cells: organ-specific sentinels of liver immune homeostasis and physiopathology. Front. Immunol. 10, 946. doi:10.3389/fimmu.2019.00946

PubMed Abstract | CrossRef Full Text | Google Scholar

Mogler, C., Wieland, M., König, C., Hu, J., Runge, A., Korn, C., et al. (2015). Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage. EMBO Mol. Med. 7 (3), 332–338. doi:10.15252/emmm.201404246

PubMed Abstract | CrossRef Full Text | Google Scholar

Mortezaee, K. (2018). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) and liver fibrosis: a review. Cell Biochem. and Funct. 36, 292–302. doi:10.1002/cbf.3351

PubMed Abstract | CrossRef Full Text | Google Scholar

Mühlbauer, M., Bosserhoff, A. K., Hartmann, A., Thasler, W. E., Weiss, T. S., Herfarth, H., et al. (2003). A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-Related liver disease. Gastroenterology 125 (4), 1085–1093. doi:10.1016/s0016-5085(03)01213-7

PubMed Abstract | CrossRef Full Text | Google Scholar

Ni, X. X., Ji, P. X., Chen, Y. X., Li, X. Y., Sheng, L., Lian, M., et al. (2022). Regulation of the macrophage-hepatic stellate cell interaction by targeting macrophage peroxisome proliferator-activated receptor gamma to prevent non-alcoholic steatohepatitis progression in mice. Liver Int. 42 (12), 2696–2712. doi:10.1111/liv.15441

PubMed Abstract | CrossRef Full Text | Google Scholar

Nojima, H., Freeman, C. M., Schuster, R. M., Japtok, L., Kleuser, B., Edwards, M. J., et al. (2016). Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate. J. Hepatol. 64 (1), 60–68. doi:10.1016/j.jhep.2015.07.030

PubMed Abstract | CrossRef Full Text | Google Scholar

O'Hara, S. P., Karlsen, T. H., and LaRusso, N. F. (2017). Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link? Gut 66 (11), 1873–1877. doi:10.1136/gutjnl-2017-314249

PubMed Abstract | CrossRef Full Text | Google Scholar

Omenetti, A., Syn, W. K., Jung, Y., Francis, H., Porrello, A., Witek, R. P., et al. (2009). Repair-related activation of hedgehog signaling promotes cholangiocyte chemokine production. Hepatology 50 (2), 518–527. doi:10.1002/hep.23019

PubMed Abstract | CrossRef Full Text | Google Scholar

Orecchioni, M., Ghosheh, Y., Pramod, A. B., and Ley, K. (2019). Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages. Front. Immunol. 10, 1084. doi:10.3389/fimmu.2019.01084

CrossRef Full Text | Google Scholar

Osei-Bordom, D., Bozward, A. G., and Oo, Y. H. (2020). The hepatic microenvironment and regulatory T cells. Cell Immunol. 357, 104195. doi:10.1016/j.cellimm.2020.104195

PubMed Abstract | CrossRef Full Text | Google Scholar

Pan, Q., Gao, M., Kim, D., Ai, W., Yang, W., Jiang, W., et al. (2024). Hepatocyte FoxO1 deficiency protects from liver fibrosis via reducing inflammation and TGF-β1-mediated HSC activation. Cell Mol. Gastroenterol. Hepatol. 17 (1), 41–58. doi:10.1016/j.jcmgh.2023.08.013

PubMed Abstract | CrossRef Full Text | Google Scholar

Park, O., Jeong, W. I., Wang, L., Wang, H., Lian, Z. X., Gershwin, M. E., et al. (2009). Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology 49, 1683–1694. doi:10.1002/hep.22813

PubMed Abstract | CrossRef Full Text | Google Scholar

Patel, A. M., Liu, Y. S., Davies, S. P., Brown, R. M., Kelly, D. A., Scheel-Toellner, D., et al. (2021). The role of B cells in adult and paediatric liver injury. Front. Immunol. 12, 729143. doi:10.3389/fimmu.2021.729143

PubMed Abstract | CrossRef Full Text | Google Scholar

Payen, V. L., Lavergne, A., Alevra Sarika, N., Colonval, M., Karim, L., Deckers, M., et al. (2021). Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep. 3 (3), 100278. doi:10.1016/j.jhepr.2021.100278

PubMed Abstract | CrossRef Full Text | Google Scholar

Peng, H., Zhu, E., and Zhang, Y. (2022). Advances of cancer-associated fibroblasts in liver cancer. Biomark. Res. 10, 59. doi:10.1186/s40364-022-00406-z

PubMed Abstract | CrossRef Full Text | Google Scholar

Peng, Y., Li, Z., Chen, S., and Zhou, J. (2021). DHFR silence alleviated the development of liver fibrosis by affecting the crosstalk between hepatic stellate cells and macrophages. J. Cell Mol. Med. 25 (21), 10049–10060. doi:10.1111/jcmm.16935

PubMed Abstract | CrossRef Full Text | Google Scholar

Petrescu, A. D., Grant, S., Williams, E., An, S. Y., Seth, N., Shell, M., et al. (2022). Leptin enhances hepatic fibrosis and inflammation in a mouse model of cholestasis. Am. J. Pathol. 192 (3), 484–502. doi:10.1016/j.ajpath.2021.11.008

PubMed Abstract | CrossRef Full Text | Google Scholar

Petrescu, A. D., Grant, S., Williams, E., Frampton, G., Parks, N., Blaney, H., et al. (2020). Coordinated targeting of galanin receptors on cholangiocytes and hepatic stellate cells ameliorates liver fibrosis in multidrug resistance protein 2 knockout mice. Am. J. Pathol. 190 (3), 586–601. doi:10.1016/j.ajpath.2019.10.023

PubMed Abstract | CrossRef Full Text | Google Scholar

Poisson, J., Lemoinne, S., Boulanger, C., Durand, F., Moreau, R., Valla, D., et al. (2017). Liver sinusoidal endothelial cells: physiology and role in liver diseases. J. Hepatol. 66 (1), 212–227. doi:10.1016/j.jhep.2016.07.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Popov, Y., Sverdlov, D. Y., Bhaskar, K. R., Sharma, A. K., Millonig, G., Patsenker, E., et al. (2010). Macrophage-mediated phagocytosis of apoptotic cholangiocytes contributes to reversal of experimental biliary fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G323–G334. doi:10.1152/ajpgi.00394.2009

PubMed Abstract | CrossRef Full Text | Google Scholar

Povero, D., Panera, N., Eguchi, A., Johnson, C. D., Papouchado, B. G., de Araujo Horcel, L., et al. (2015). Lipid-induced hepatocyte-derived extracellular vesicles regulate hepatic stellate cell via microRNAs targeting PPAR-γ. Cell Mol. Gastroenterol. Hepatol. 1 (6), 646–663. doi:10.1016/j.jcmgh.2015.07.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Pradere, J. P., Kluwe, J., De Minicis, S., Jiao, J. J., Gwak, G. Y., Dapito, D. H., et al. (2013). Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58 (4), 1461–1473. doi:10.1002/hep.26429

PubMed Abstract | CrossRef Full Text | Google Scholar

Pusl, T., Wild, N., Vennegeerts, T., Wimmer, R., Göke, B., Brand, S., et al. (2008). Free fatty acids sensitize hepatocytes to bile acid-induced apoptosis. Biochem. Biophys. Res. Commun. 371 (3), 441–445. doi:10.1016/j.bbrc.2008.04.113

PubMed Abstract | CrossRef Full Text | Google Scholar

Pydyn, N., Ferenc, A., Trzos, K., Pospiech, E., Wilamowski, M., Mucha, O., et al. (2024). MCPIP1 inhibits hepatic stellate cell activation in autocrine and paracrine manners, preventing liver fibrosis. Cell Mol. Gastroenterol. Hepatol. 17 (6), 887–906. doi:10.1016/j.jcmgh.2024.01.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Radaeva, S., Sun, R., Jaruga, B., Nguyen, V. T., Tian, Z., and Gao, B. (2006). Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 130 (2), 435–452. doi:10.1053/j.gastro.2005.10.055

PubMed Abstract | CrossRef Full Text | Google Scholar

Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., et al. (2019). Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575 (7783), 512–518. doi:10.1038/s41586-019-1631-3

PubMed Abstract | CrossRef Full Text | Google Scholar

Ramachandran, P., Pellicoro, A., Vernon, M. A., Boulter, L., Aucott, R. L., Ali, A., et al. (2012). Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl. Acad. Sci. U. S. A. 109 (46), E3186–E3195. doi:10.1073/pnas.1119964109

PubMed Abstract | CrossRef Full Text | Google Scholar

Reißing, J., Berres, M., Strnad, P., Wree, A., Inzaugarat, M. E., Trautwein, C., et al. (2024). Th2 cell activation in chronic liver disease is driven by local IL33 and contributes to IL13-Dependent fibrogenesis. Cell Mol. Gastroenterol. Hepatol. 17 (4), 517–538. doi:10.1016/j.jcmgh.2023.12.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Rosenthal, S. B., Liu, X., Ganguly, S., Dhar, D., Pasillas, M. P., Ricciardelli, E., et al. (2021). Heterogeneity of HSCs in a mouse model of NASH. Hepatology 74 (2), 667–685. doi:10.1002/hep.31743

PubMed Abstract | CrossRef Full Text | Google Scholar

Ruf, B., Catania, V. V., Wabitsch, S., Ma, C., Diggs, L. P., Zhang, Q., et al. (2021). Activating mucosal-associated invariant T cells induces a broad antitumor response. Cancer Immunol. Res. 9 (9), 1024–1034. doi:10.1158/2326-6066.CIR-20-0925

PubMed Abstract | CrossRef Full Text | Google Scholar

Salhab, A., Amer, J., Lu, Y., and Safadi, R. (2022). Sodium+/Taurocholate cotransporting polypeptide as target therapy for liver fibrosis. Gut 71 (7), 1373–1385. doi:10.1136/gutjnl-2020-323345

PubMed Abstract | CrossRef Full Text | Google Scholar

Satoh, T., Nakagawa, K., Sugihara, F., Kuwahara, R., Ashihara, M., Yamane, F., et al. (2017). Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature 541 (7635), 96–101. doi:10.1038/nature20611

CrossRef Full Text | Google Scholar

Scott, C. L., and Guilliams, M. (2018). The role of kupffer cells in hepatic iron and lipid metabolism. J. Hepatology 69, 1197–1199. doi:10.1016/j.jhep.2018.02.013

PubMed Abstract | CrossRef Full Text | Google Scholar

Seidl, C. I., Stricker, S. H., and Barlow, D. P. (2006). The imprinted air ncRNA is an atypical RNAPII transcript that evades splicing and escapes nuclear export. EMBO J. 25 (15), 3565–3575. doi:10.1038/sj.emboj.7601245

PubMed Abstract | CrossRef Full Text | Google Scholar

Seo, W., Eun, H. S., Kim, S. Y., Yi, H. S., Lee, Y. S., Park, S. H., et al. (2016). Exosome-mediated activation of toll-like receptor 3 in stellate cells stimulates interleukin-17 production by γδ T cells in liver fibrosis. Hepatology 64 (2), 616–631. doi:10.1002/hep.28644

PubMed Abstract | CrossRef Full Text | Google Scholar

Shapouri-Moghaddam, A., Mohammadian, S., Vazini, H., Taghadosi, M., Esmaeili, S. A., Mardani, F., et al. (2018). Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiology 233, 6425–6440. doi:10.1002/jcp.26429

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, H., Wang, X., Li, F., Gerlach, B. D., Yurdagul, A., Moore, M. P., et al. (2022). CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis. Sci. Transl. Med. 14 (672), eabp8309. doi:10.1126/scitranslmed.abp8309

PubMed Abstract | CrossRef Full Text | Google Scholar

Shi, J., Zhao, J., Zhang, X., Cheng, Y., Hu, J., Li, Y., et al. (2017). Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients. Sci. Rep. 7, 44544. doi:10.1038/srep44544

PubMed Abstract | CrossRef Full Text | Google Scholar

Shiri, A. M., Zhang, T., Bedke, T., Zazara, D. E., Zhao, L., Lücke, J., et al. (2024). IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J. Hepatol. 80 (4), 634–644. doi:10.1016/j.jhep.2023.12.015

PubMed Abstract | CrossRef Full Text | Google Scholar

Slijepcevic, D., and van de Graaf, S. F. (2017). Bile acid uptake transporters as targets for therapy. Dig. Dis. 35 (3), 251–258. doi:10.1159/000450983

PubMed Abstract | CrossRef Full Text | Google Scholar

Staels, B., Rubenstrunk, A., Noel, B., Rigou, G., Delataille, P., Millatt, L. J., et al. (2013). Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58, 1941–1952. doi:10.1002/hep.26461

PubMed Abstract | CrossRef Full Text | Google Scholar

Su, Q., Kumar, V., Sud, N., and Mahato, R. I. (2018). MicroRNAs in the pathogenesis and treatment of progressive liver injury in NAFLD and liver fibrosis. Adv. Drug Deliv. Rev. 129, 54–63. doi:10.1016/j.addr.2018.01.009

PubMed Abstract | CrossRef Full Text | Google Scholar

Sun, J., Wu, M., Wang, L., Wang, P., Xiao, T., Wang, S., et al. (2022). miRNA-21, which disrupts metabolic reprogramming to facilitate CD4+ T cell polarization toward the Th2 phenotype, accelerates arsenite-induced hepatic fibrosis. Ecotoxicol. Environ. Saf. 248 (36427370.1), 114321. doi:10.1016/j.ecoenv.2022.114321

PubMed Abstract | CrossRef Full Text | Google Scholar

Sung, S., Kim, J., and Jung, Y. (2018). Liver-derived exosomes and their implications in liver pathobiology. Int. J. Mol. Sci. 19 (12), 3715. doi:10.3390/ijms19123715

PubMed Abstract | CrossRef Full Text | Google Scholar

Sutti, S., and Albano, E. (2020). Adaptive immunity: an emerging player in the progression of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 17 (2), 81–92. doi:10.1038/s41575-019-0210-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Swadling, L., Pallett, L. J., Diniz, M. O., Baker, J. M., Amin, O. E., Stegmann, K. A., et al. (2020). Human liver memory CD8+ T cells use autophagy for tissue residence. Cell Rep. 30 (3), 687–698. doi:10.1016/j.celrep.2019.12.050

PubMed Abstract | CrossRef Full Text | Google Scholar

Tacke, F., and Zimmermann, H. W. (2014). Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60 (5), 1090–1096. doi:10.1016/j.jhep.2013.12.025

PubMed Abstract | CrossRef Full Text | Google Scholar

Tao, X., Zhang, R., Du, R., Yu, T., Yang, H., Li, J., et al. (2022). EP3 enhances adhesion and cytotoxicity of NK cells toward hepatic stellate cells in a murine liver fibrosis model. J. Exp. Med. 219, e20212414. doi:10.1084/jem.20212414

PubMed Abstract | CrossRef Full Text | Google Scholar

Tatemoto, K., Hosoya, M., Habata, Y., Fujii, R., Kakegawa, T., Zou, M. X., et al. (1998). Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251 (2), 471–476. doi:10.1006/bbrc.1998.9489

PubMed Abstract | CrossRef Full Text | Google Scholar

Thapa, M., Chinnadurai, R., Velazquez, V. M., Tedesco, D., Elrod, E., Han, J. H., et al. (2015). Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. Hepatology 61 (6), 2067–2079. doi:10.1002/hep.27761

PubMed Abstract | CrossRef Full Text | Google Scholar

Trampuž, S. R., van Riet, S., Nordling, Å., and Ingelman-Sundberg, M. (2023). The role of CTGF in liver fibrosis induced in 3D human liver spheroids. Cells 12, 302. doi:10.3390/cells12020302

PubMed Abstract | CrossRef Full Text | Google Scholar

Trinh, V. Q., Lee, T. F., Lemoinne, S., Ray, K. C., Ybanez, M. D., Tsuchida, T., et al. (2023). Hepatic stellate cells maintain liver homeostasis through paracrine neurotrophin-3 signaling that induces hepatocyte proliferation. Sci. Signal 16 (787), eadf6696. doi:10.1126/scisignal.adf6696

PubMed Abstract | CrossRef Full Text | Google Scholar

Tsuchida, T., and Friedman, S. L. (2017). Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14 (7), 397–411. doi:10.1038/nrgastro.2017.38

PubMed Abstract | CrossRef Full Text | Google Scholar

Turaga, R. C., Satyanarayana, G., Sharma, M., Yang, J. J., Wang, S., Liu, C., et al. (2021). Targeting integrin αvβ3 by a rationally designed protein for chronic liver disease treatment. Commun. Biol. 4 (1), 1087. doi:10.1038/s42003-021-02611-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Visentini, M., and Colantuono, S. (2022). “B cell in health and disease,” in Paraproteinemia and related disorders. Editors G. Ragab, L. Quartuccio, and H. Goubran (Cham: Springer).

Google Scholar

Wang, J., Fa, J., Wang, P., Jia, X., Peng, H., Chen, J., et al. (2017a). NINJ2- A novel regulator of endothelial inflammation and activation. Cell Signal 35, 231–241. doi:10.1016/j.cellsig.2017.04.011

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, L., Li, D., Zhu, Z., Liao, Y., Wu, J., Liu, Y., et al. (2023c). Knockout of Sema4D alleviates liver fibrosis by suppressing AOX1 expression. Pharmacol. Res. 195, 106886. doi:10.1016/j.phrs.2023.106886

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, L., Wang, Y., and Quan, J. (2020a). Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy. Mol. Med. 26, 81. doi:10.1186/s10020-020-00207-w

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, R., Ding, Q., Yaqoob, U., de Assuncao, T. M., Verma, V. K., Hirsova, P., et al. (2015). Exosome adherence and internalization by hepatic stellate cells triggers sphingosine 1-Phosphate-dependent migration. J. Biol. Chem. 290 (52), 30684–30696. doi:10.1074/jbc.M115.671735

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, S., Gao, J., Yang, M., Zhang, G., Yin, L., and Tong, X. (2024). OPN-mediated crosstalk between hepatocyte E4BP4 and hepatic stellate cells promotes MASH-associated liver fibrosis. Adv. Sci. (Weinh) 11 (47), e2405678. doi:10.1002/advs.202405678

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, S., Li, K., Pickholz, E., Dobie, R., Matchett, K. P., Henderson, N. C., et al. (2023b). An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci. Transl. Med. 15 (677), eadd3949. doi:10.1126/scitranslmed.add3949

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, X. M., Holz, L. E., Chowdhury, S., Cordoba, S. P., Evans, K. A., Gall, M. G., et al. (2017c). The pro-fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride-induced experimental liver injury. Immunol. Cell Biol. 95 (5), 443–453. doi:10.1038/icb.2016.116

CrossRef Full Text | Google Scholar

Wang, Y., Aoki, H., Yang, J., Peng, K., Liu, R., Li, X., et al. (2017b). The role of sphingosine 1-phosphate receptor 2 in bile-acid-induced cholangiocyte proliferation and cholestasis-induced liver injury in mice. Hepatology 65 (6), 2005–2018. doi:10.1002/hep.29076

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Y., Chen, C., Deng, Z., Bian, E., Huang, C., Lei, T., et al. (2017d). Repression of TSC1/TSC2 mediated by MeCP2 regulates human embryo lung fibroblast cell differentiation and proliferation. Int. J. Biol. Macromol. 96, 578–588. doi:10.1016/j.ijbiomac.2016.12.062

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Y., Liu, J., Burrows, P. D., and Wang, J. Y. (2020b). B cell development and maturation. Adv. Exp. Med. Biol. 1254, 1–22. doi:10.1007/978-981-15-3532-1_1

PubMed Abstract | CrossRef Full Text | Google Scholar

Wang, Y., Wang, P., Yu, Y., Huang, E., Yao, Y., Guo, D., et al. (2023a). Hepatocyte Ninjurin2 promotes hepatic stellate cell activation and liver fibrosis through the IGF1R/EGR1/PDGF-BB signaling pathway. Metabolism 140, 155380. doi:10.1016/j.metabol.2022.155380

PubMed Abstract | CrossRef Full Text | Google Scholar

Watanabe, A., Hashmi, A., Gomes, D. A., Town, T., Badou, A., Flavell, R. A., et al. (2007). Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 46 (5), 1509–1518. doi:10.1002/hep.21867

PubMed Abstract | CrossRef Full Text | Google Scholar

Wehr, A., Baeck, C., Heymann, F., Niemietz, P. M., Hammerich, L., Martin, C., et al. (2013). Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J. Immunol. 190, 5226–5236. doi:10.4049/jimmunol.1202909

PubMed Abstract | CrossRef Full Text | Google Scholar

Wei, S., Zhou, H., Wang, Q., Zhou, S., Li, C., Liu, R., et al. (2019). RIP3 deficiency alleviates liver fibrosis by inhibiting ROCK1-TLR4-NF-κB pathway in macrophages. FASEB J. 33, 11180–11193. doi:10.1096/fj.201900752R

PubMed Abstract | CrossRef Full Text | Google Scholar

Wermuth, P. J., and Jimenez, S. A. (2015). The significance of macrophage polarization subtypes for animal models of tissue fibrosis and human fibrotic diseases. Clin. Transl. Med. 4, 2. doi:10.1186/s40169-015-0047-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Wu, M., Sun, J., Wang, L., Wang, P., Xiao, T., Wang, S., et al. (2023). The lncRNA HOTAIR via miR-17-5p is involved in arsenite-induced hepatic fibrosis through regulation of Th17 cell differentiation. J. Hazard Mater 443 (Pt B), 130276. doi:10.1016/j.jhazmat.2022.130276

PubMed Abstract | CrossRef Full Text | Google Scholar

Wu, X., Shu, L., Zhang, Z., Li, J., Zong, J., Cheong, L. Y., et al. (2021). Adipocyte fatty acid binding protein promotes the onset and progression of liver fibrosis via mediating the crosstalk between liver sinusoidal endothelial cells and hepatic stellate cells. Adv. Sci. (Weinh) 8 (11), e2003721. doi:10.1002/advs.202003721

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, G., Jiang, R., Wang, X., Liu, P., Zhao, A., Wu, Y., et al. (2021). Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis. EBioMedicine 66, 103290. doi:10.1016/j.ebiom.2021.103290

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, G., Wang, X., Wang, L., Wang, L., Atkinson, R. D., Kanel, G. C., et al. (2012). Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142 (4), 918–927. doi:10.1053/j.gastro.2011.12.017

PubMed Abstract | CrossRef Full Text | Google Scholar

Xie, Y., Huang, Y., Li, Z. Y., Jiang, W., Shi, N. X., Lu, Y., et al. (2024). Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA+ B cells. Mol. Cancer 23 (1), 95. doi:10.1186/s12943-024-02001-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Xiong, X., Kuang, H., Ansari, S., Liu, T., Gong, J., Wang, S., et al. (2019). Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis. Mol. Cell 75 (3), 644–660. doi:10.1016/j.molcel.2019.07.028

CrossRef Full Text | Google Scholar

Yamanaka, M., Shegogue, D., Pei, H., Bu, S., Bielawska, A., Bielawski, J., et al. (2004). Sphingosine kinase 1 (SPHK1) is induced by transforming growth factor-beta and mediates TIMP-1 up-regulation. J. Biol. Chem. 279 (52), 53994–54001. doi:10.1074/jbc.M410144200

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, J., Liu, Q., Cao, S., Xu, T., Li, X., Zhou, D., et al. (2018). MicroRNA-145 increases the apoptosis of activated hepatic stellate cells induced by TRAIL through NF-κB signaling pathway. Front. Pharmacol. 8, 980. doi:10.3389/fphar.2017.00980

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, J., Tang, X., Liang, Z., Chen, M., and Sun, L. (2023a). Taurocholic acid promotes hepatic stellate cell activation via S1PR2/p38 MAPK/YAP signaling under cholestatic conditions. Clin. Mol. Hepatol. 29 (2), 465–481. doi:10.3350/cmh.2022.0327

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, L., Yue, S., Yang, L., Liu, X., Han, Z., Zhang, Y., et al. (2013). Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis. J. Hepatol. 59 (1), 114–123. doi:10.1016/j.jhep.2013.02.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, W., He, H., Wang, T., Su, N., Zhang, F., Jiang, K., et al. (2021). Single-cell transcriptomic analysis reveals a hepatic stellate cell-activation roadmap and myofibroblast origin during liver fibrosis in mice. Hepatology 74 (5), 2774–2790. doi:10.1002/hep.31987

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, W. C., Hwang, Y. S., Chen, Y. Y., Liu, C. L., Shen, C. N., Hong, W. H., et al. (2017). Interleukin-4 supports the suppressive immune responses elicited by regulatory T cells. Front. Immunol. 8, 1508. doi:10.3389/fimmu.2017.01508

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, Y., Sheng, Y., Wang, J., Zhou, X., Li, W., Zhang, C., et al. (2023b). Corrigendum: double-Negative T cells regulate hepatic stellate cell activation to promote liver fibrosis progression via NLRP3. Front. Immunol. 14, 1340576. doi:10.3389/fimmu.2023.1340576

PubMed Abstract | CrossRef Full Text | Google Scholar

Yang, Y. M., Noureddin, M., Liu, C., Ohashi, K., Kim, S. Y., Ramnath, D., et al. (2019). Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Sci. Transl. Med. 11 (496), eaat9284. doi:10.1126/scitranslmed.aat9284

PubMed Abstract | CrossRef Full Text | Google Scholar

Yao, Y., Zuo, X., Shao, F., Yu, K., and Liang, Q. (2024). Jaceosidin attenuates the progression of hepatic fibrosis by inhibiting the VGLL3/HMGB1/TLR4 signaling pathway. Phytomedicine 128, 155502. doi:10.1016/j.phymed.2024.155502

PubMed Abstract | CrossRef Full Text | Google Scholar

Ye, Q., Zhou, Y., Zhao, C., Xu, L., and Ping, J. (2021). Salidroside inhibits CCl4-Induced liver fibrosis in mice by reducing activation and migration of HSC induced by liver sinusoidal endothelial cell-derived exosomal SphK1. Front. Pharmacol. 12, 677810. doi:10.3389/fphar.2021.677810

PubMed Abstract | CrossRef Full Text | Google Scholar

Yi, H. S., Lee, Y. S., Byun, J. S., Seo, W., Jeong, J. M., Park, O., et al. (2014). Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. Hepatology 60, 1044–1053. doi:10.1002/hep.27137

PubMed Abstract | CrossRef Full Text | Google Scholar

Yimlamai, D., Christodoulou, C., Galli, G. G., Yanger, K., Pepe-Mooney, B., Gurung, B., et al. (2014). Hippo pathway activity influences liver cell fate. Cell 157 (6), 1324–1338. doi:10.1016/j.cell.2014.03.060

PubMed Abstract | CrossRef Full Text | Google Scholar

Yong, Q., Huang, C., Chen, B., An, J., Zheng, Y., Zhao, L., et al. (2024). Gentiopicroside improves NASH and liver fibrosis by suppressing TLR4 and NLRP3 signaling pathways. Biomed. Pharmacother. 177, 116952. doi:10.1016/j.biopha.2024.116952

CrossRef Full Text | Google Scholar

Younossi, Z. M., Golabi, P., de Avila, L., Paik, J. M., Srishord, M., Fukui, N., et al. (2019). The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J. Hepatol. 71 (4), 793–801. doi:10.1016/j.jhep.2019.06.021

PubMed Abstract | CrossRef Full Text | Google Scholar

Yu, J. H., Choi, M. G., Lee, N. Y., Kwon, A., Lee, E., and Koo, J. H. (2024). Hepatocyte GPCR signaling regulates IRF3 to control hepatic stellate cell transdifferentiation. Cell Commun. Signal 22 (1), 48. doi:10.1186/s12964-023-01416-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Yu, K., Li, N., Cheng, Q., Zheng, J., Zhu, M., Bao, S., et al. (2018). miR-96-5p prevents hepatic stellate cell activation by inhibiting autophagy via ATG7. J. Mol. Med. 96, 65–74. doi:10.1007/s00109-017-1593-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, F., Jiang, W. W., Li, X., Qiu, X. Y., Wu, Z., Chi, Y. J., et al. (2016). Role of intrahepatic B cells in non-alcoholic fatty liver disease by secreting pro-inflammatory cytokines and regulating intrahepatic T cells. J. Dig. Dis. 17 (7), 464–474. doi:10.1111/1751-2980.12362

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, J., Jiang, N., Ping, J., and Xu, L. (2021a). TGF-β1-induced autophagy activates hepatic stellate cells via the ERK and JNK signaling pathways. Int. J. Mol. Med. 47, 256–266. doi:10.3892/ijmm.2020.4778

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, J. P., Yan, J., Xu, J., Pang, X. H., Chen, M. S., Li, L., et al. (2009). Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J. Hepatol. 50 (5), 980–989. doi:10.1016/j.jhep.2008.12.033

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, L., Tao, M., Zhang, H., Zhang, S., Hou, X., Zong, C., et al. (2024). Lipopolysaccharide modification enhances the inhibitory effect of clodronate liposomes on hepatic fibrosis by depletion of macrophages and hepatic stellate cells. Chem. Biol. Interact. 395, 111015. doi:10.1016/j.cbi.2024.111015

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, W., Conway, S. J., Liu, Y., Snider, P., Chen, H., Gao, H., et al. (2021b). Heterogeneity of hepatic stellate cells in fibrogenesis of the liver: insights from single-cell transcriptomic analysis in liver injury. Cells 10 (8), 2129. doi:10.3390/cells10082129

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhao, Y., He, W., Wang, C., Cui, N., Yang, C., You, Z., et al. (2022). Characterization of intrahepatic B cells in acute-on-chronic liver failure. Front. Immunol. 13, 1041176. doi:10.3389/fimmu.2022.1041176

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhao, Z., Yin, L., Wu, F., and Tong, X. (2021). Hepatic metabolic regulation by nuclear factor E4BP4. J. Mol. Endocrinol. 66 (1), R15–R21. doi:10.1530/JME-20-0239

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, D. D., Wang, X., Wang, Y., Xiang, X. J., Liang, Z. C., Zhou, Y., et al. (2016). MicroRNA-145 inhibits hepatic stellate cell activation and proliferation by targeting ZEB2 through Wnt/β-catenin pathway. Mol. Immunol. 75, 151–160. doi:10.1016/j.molimm.2016.05.018

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhou, X., Yu, L., Zhou, M., Hou, P., Yi, L., and Mi, M. (2021). Dihydromyricetin ameliorates liver fibrosis via inhibition of hepatic stellate cells by inducing autophagy and natural killer cell-mediated killing effect. Nutr. Metab. 18, 64. doi:10.1186/s12986-021-00589-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Glossary

HSC Hepatic stellate cell

LSECs Liver sinusoidal endothelial cells

MMP Matrix metalloproteinases

ILTC Innate lymphocyte populations

P2Y14 Purinergic Receptor P2Y14

TGF-β Transforming growth factor-β

OPN Osteopontin

EN Endosialin

MdM Monocyte-derived macrophage

MASH Metabolic dysfunction-associated steatohepatitis

LAM Lipid-associated macrophage

CTGF Connective tissue growth factor

ECM Extracellular matrix

BMDMs Bone marrow-derived macrophages

CCL2 Chemokine C-C motif ligand 2

MAPK Mitogen-activated protein kinase

NLRP3 NOD-like receptor family pyrin domain containing 3

MAIT Mucosal-Associated Invariant T cell in liver diseases

GARP Glycoprotein A repetitions predominant

A-FABP Adipocyte Fatty Acid Binding Protein

S1P Sphingosine-1-phosphate

SphK1 Sphingosine Kinase 1

AIRN Antisense Of IGF2R Non-Protein Coding RNA

KLF2 Kruppel-like factor 2

POFUT1 Protein O-fucosyltransferase

Zeb2 Zinc-finger E-box-binding homeobox2

IGF1 Insulin-like growth factor-1

DAMPs Damage-associated molecular modules

HMGB1 High Mobility Group Box-1

NTCP Sodium+/taurocholate cotransporting polypeptide

HCC Hepatocyte carcinoma

EV Extracellular vesicles

NASH Non-alcoholic steatohepatitis

NAFLD Non-alcoholic fatty liver disease

FoxO1 Forkhead transcription factor 1

EMT Epithelial-mesenchymal transition

E4BP4 E4-binding protein 4

MDR2 Multidrug resistance protein 2

EZH2 Enhancer of zeste homologue 2

CAF Cancer-associated fibroblasts

iCCA Intrahepatic cholangiocarcinoma

MCP-1 Monocyte chemotactic protein-1

Fn Fibronectin

CCL C-C Motif Chemokine Ligand

Gpnmb Glycoprotein NMB

PD-L1 Programmed death ligand 1

TLR Toll like receptor

DNTs Double-negative T-cells

CAR Chimeric antigen receptor

HGF Hepatocyte growth factor