Research and application of medicines for treating liver fibrosis: current status and prospects

Abstract

Ethnopharmacological Relevance:

Liver fibrosis is a common pathological consequence of multiple chronic liver diseases, making its pharmacological management a key area of medical research. Diverse classes of therapeutic agents offer distinct advantages and limitations. Notably, combination therapy has emerged as a prominent focus of contemporary investigation due to its potential to enhance treatment outcomes.

Materials and Methods:

As of 1 February 2025, a comprehensive literature search was conducted using PubMed and Web of Science, employing keywords related to liver fibrosis and its treatment. In accordance with ConPhyMP guidelines, one author assessed the quality of studies involving botanical drug metabolites.

Results:

This review synthesizes findings from 111 research articles, offering an overview of two primary classes of therapeutic agents and their integration with emerging technologies-namely mesenchymal stem cell-derived exosomes and nanoparticles. On one side, it discusses biomedicine-related therapies, including conventional biomedicine medicines, repurposed drugs, and investigational compounds. On the other, it addresses botanical-based treatments, encompassing traditional Chinese medicine (TCM) formulas and botanical drug metabolites. Both categories have shown promising therapeutic efficacy in clinical and preclinical settings.

Conclusion:

This review provides a comprehensive and detailed overview of pharmacological strategies for the treatment of liver fibrosis, shows the application and research status of different types of medicines, and provides a comprehensive perspective for current research directions. It points out the limitations of existing research and suggests that the clinical research of various medicines and combination therapies should be strengthened in the future, and the liver fibrosis model should be optimized to promote clinical transformation, which provides an important reference for future research directions.

1 Introduction

Liver fibrosis is a complex pathological response to chronic hepatic injury, characterized by the activation of hepatic stellate cells (HSCs) and excessive extracellular matrix (ECM) deposition, ultimately leading to fibrous tissue formation (Zhang et al., 2021). It represents the liver’s wound-healing mechanism in response to sustained damage and is a shared pathological endpoint across a spectrum of chronic liver diseases, including viral hepatitis and non-alcoholic fatty liver disease (NAFLD) (Henderson et al., 2020)—the latter now recognized as the most prevalent liver disease globally (Kuchay et al., 2020). The extent of hepatic fibrosis is a critical predictor of prognosis and mortality in chronic liver conditions, contributing significantly to global disease burden, healthcare costs, and the rising incidence of cirrhosis-related complications (O'Hara et al., 2020; Sanyal et al., 2023).

Despite its clinical importance, effective treatment of liver fibrosis remains challenging due to its multifactorial and dynamic pathogenesis, which involves complex signaling pathways and pro-fibrotic mediators such as transforming growth factor-beta (TGF-β) (Roehlen et al., 2020). Although several biomedicine pharmacological agents have been developed for liver fibrosis secondary to chronic liver diseases, their efficacy is often suboptimal, and adverse effects are common. Furthermore, many repurposed drugs that show promise in preclinical models have failed to yield meaningful outcomes in clinical trials (Gilgenkrantz et al., 2021). In contrast, certain Traditional Chinese Medicine (TCM) formulas have demonstrated definitive anti-fibrotic effects and are currently approved for clinical use in China (Li, 2020). Additionally, innovative drug delivery strategies—such as mesenchymal stem cell-derived exosomes (MSC-ex) and nanoparticles (NPs)—are being explored to improve hepatic targeting, enhance therapeutic efficacy, and reduce systemic toxicity (Feng et al., 2024; Liu J. et al., 2024).

This review presents a synthesis of recent advances in liver fibrosis treatment, drawing from studies published in the PubMed and Web of Science databases within the past 3 years. It systematically examines developments in biomedicine pharmacotherapy, drug repurposing, novel molecular candidates, botanical metabolites, and TCM-based interventions. These findings highlight the expanding landscape of anti-fibrotic strategies and the growing importance of integrative approaches. In particular, the convergence of MSC-ex and NP technologies with pharmacological agents represents a promising frontier in precision liver therapy. This paper aims to provide a comprehensive overview of current treatment modalities and to identify emerging directions for future research (Figure 1).

FIGURE 1

2 Methods

A systematic literature review was conducted as of 1 February 2025, encompassing both in vitro and in vivo experimental studies retrieved from PubMed and Web of Science. The search employed keywords such as liver fibrosis, treatment, and Traditional Chinese Medicine. Inclusion criteria were: (1) studies addressing the therapeutic effects or mechanisms of pharmacological agents in liver fibrosis using any combination of the specified keywords; (2) studies presenting original experimental data with clearly defined methodologies; and (3) full-text articles published in English. Exclusion criteria included duplicate records, irrelevant studies based on title and abstract screening, and publications lacking mechanistic insight or sufficient methodological detail. Based on these criteria, 102 studies were selected for analysis. Of these, 18 studies focusing on botanical drug metabolites were further evaluated for methodological quality using the ConPhyMP assessment tool. The evaluation was jointly performed by authors ZJ and LYX, with detailed results provided in the supplementary materials.

3 Pathological mechanisms of hepatic fibrosis

The progression of liver fibrosis is marked by the excessive accumulation of extracellular matrix (ECM) components (Iredale, 2007). Etiological factors such as toxins, metabolic disorders, or viral infections cause hepatocyte damage and immune cell infiltration, which, in turn, activate hepatic stellate cells (HSCs) and promote their differentiation into collagen-producing myofibroblasts (Zhang et al., 2016). Under physiological conditions, ECM synthesis and degradation remain in dynamic balance. However, in chronic liver disease, this balance is disrupted, favoring pro-fibrotic over anti-fibrotic signals. This shift induces myofibroblast proliferation, migration, contraction, and excessive ECM deposition. Moreover, vascular endothelial growth factor A (VEGFA) promotes pathological angiogenesis during fibrosis progression (Elpek, 2014; Shen H. et al., 2022). While producing ECM, activated HSCs also secrete matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), the latter suppressing MMP activity and further reducing ECM degradation (Tacke and Zimmermann, 2014). In parallel, hepatocyte apoptosis and the release of damage-associated molecular patterns (DAMPs) directly stimulate HSC activation and initiate immune cell recruitment, including lymphocytes and macrophages. Kupffer cells, the liver-resident macrophages, can polarize into M1 or M2 phenotypes and secrete fibrogenic mediators such as transforming growth factor-beta 1 (TGF-β1) and reactive oxygen species (ROS). These mediators, along with ROS from neutrophils, enhance HSC activation and ECM synthesis (Ramachandran et al., 2012; Krenkel and Tacke, 2017). Oxidative stress further exacerbates fibrogenesis through NADPH oxidase (NOX)-mediated ROS production and the release of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which potentiate HSC activation and fibrotic remodeling (Ren et al., 2021). Additionally, epithelial-mesenchymal transition (EMT) contributes to the myofibroblast population (Chen et al., 2020). The TGF-β signaling pathway is pivotal in initiating and sustaining HSC activation and fibrogenesis (Dewidar et al., 2019). Beyond TGF-β, multiple signaling pathways have been implicated in modulating the fibrotic response. A comprehensive overview of the pathogenic mechanisms underlying hepatic fibrosis is illustrated in Figure 2.

FIGURE 2

4 Biomedicine treatment for liver fibrosis

4.1 Biomedicine medicines treatment for liver fibrosis

Clinically, liver fibrosis is commonly associated with non-alcoholic steatohepatitis (NASH), viral hepatitis, type 2 diabetes-related fatty liver disease, and primary biliary cholangitis (PBC). Standard pharmacotherapies—such as entecavir (ETV) for chronic hepatitis B (CHB) and ursodeoxycholic acid for PBC—have shown efficacy in mitigating fibrosis (Table 1). Nonetheless, the lack of fibrosis-specific targeted therapies continues to drive drug discovery efforts (Table 2).

4.1.1 Clinical trial used anti-liver fibrosis biomedicine medicines

Resmetirom received initial regulatory approval in March 2024 for the treatment of metabolic dysfunction-associated steatohepatitis (MASH)/non-alcoholic steatohepatitis (NASH) and related fibrosis (Keam, 2024). In a phase 2 trial conducted by (Loomba et al., 2024), tirzepatide significantly improved MASH without exacerbating fibrosis after 52 weeks of treatment. In another study, (Loomba et al., 2023), evaluated pegozafermin, a fibroblast growth factor 21 (FGF21) analog, in NASH patients with moderate-to-severe fibrosis. After 24 weeks, fibrosis improvements were observed, although gastrointestinal side effects, notably nausea and diarrhea, were reported. (Sanyal et al., 2024). conducted a 48-week clinical trial assessing survodutide in patients with mild-to-moderate NASH-associated fibrosis. The drug demonstrated superiority over placebo in improving NASH features and preventing fibrosis progression, albeit with significant adverse effects. A follow-up study by (Lavynenko et al., 2022) focused on hepatic fibrosis in individuals with type 2 diabetes. In a large-scale study involving more than 3,000 patients with CHB and hepatic cirrhosis, (Chon et al., 2022), reported that ETV initially led to slight elevations in fibrosis biomarkers. However, long-term treatment (6 months–6 years) with ETV or tenofovir (TDF) yielded comparable efficacy in fibrosis reduction. The study also highlighted that combination therapy with metformin, exenatide, and pioglitazone was more effective in attenuating hepatic fibrosis than conventional stepwise regimens. Finally, in a 5-year randomized, double-blind, placebo-controlled phase 2 trial, (Israelsen et al., 2023), investigated pharmacologic interventions for patients with alcohol-related liver disease. Recent investigations suggest that Rifaximin-α may slow the progression of liver fibrosis, though this finding requires validation in forthcoming multicenter phase 3 clinical trials. At present, clinical studies have been involved in the treatment of liver fibrosis caused by several common liver diseases. However, many of these clinical trials are limited by small sample sizes, which compromises the reliability and generalizability of their findings.

4.1.2 Repurposed drugs

(Zhang et al., 2023a) reviewed therapeutic advances related to metformin in treating fatty liver disease and liver fibrosis in patients with type 2 diabetes, emphasizing both clinical potential and underlying mechanisms. (Elbaset et al., 2024). demonstrated that pitavastatin possesses anti-fibrotic properties by attenuating oxidative stress and inflammatory signaling via modulation of the NF-κB and PI3K/AKT pathways. Similarly, (Pu et al., 2023), showed that montelukast effectively reduces fibrosis in murine models by inhibiting hepatic stellate cell (HSC) activation and inflammatory responses. (Li et al., 2023c). found that axitinib mitigates liver inflammation and fibrosis through dual mechanisms: suppression of HSC activation and enhancement of mitochondrial complexes I and III function. Further evidence supports the anti-fibrotic potential of other repurposed agents. (Guo et al., 2024). reported that nimodipine alleviates hepatic inflammation and fibrosis by modulating the liver’s immune microenvironment. (Shi et al., 2023). found that calcitriol regulates HSC activation, proliferation, and differentiation by downregulating NS3TP1 expression. (Han et al., 2024).showed that tetracycline inhibits activated HSCs by targeting EphB1/2 phosphorylation and the MAPK1/2 pathway. According to (Liu K. X. et al., 2024), nitazoxanide acts on key fibrotic signaling molecules including AMPK, STAT3, and Smad2/3, with follow-up studies confirming its efficacy in ameliorating fibrosis through these mechanisms. (Sharma et al., 2024). demonstrated that yohimbine reduces fibrosis and inflammation by modulating the JNK/Wnt/β-catenin pathway. Early evidence by (Jiang et al., 2016) indicated that aspirin decreases fibrosis indices in adult chronic liver disease patients in the US (Sun et al., 2022), a mechanism later confirmed in rat models via modulation of the TGF-β/Smad pathway. (Fujiwara et al., 2024). reported that carfilzomib reduces fibrotic marker expression in HSCs and attenuates CCl₄-induced liver fibrosis. (Ying et al., 2022). identified ivermectin as an anti-fibrotic agent acting primarily through modulation of HSCs. (Zheng K. X. et al., 2023). employed molecular docking to identify dihydroergotamine as a potential TGF pathway modulator, with subsequent cellular assays confirming its anti-fibrotic effect.

Many of these agents, initially developed for unrelated conditions, demonstrate efficacy by modulating key pathogenic pathways involved in hepatic fibrosis. For example, the well-established links between diabetes, dyslipidemia, and liver fibrosis suggest that hypoglycemic and hypolipidemic drugs may exert secondary anti-fibrotic effects. However, it is important to recognize that commonly used experimental models, such as CCl₄ and TAA-induced liver fibrosis, do not fully replicate the pathophysiological complexity of human liver fibrosis. This discrepancy may hinder the direct translation of preclinical findings into clinical practice, highlighting the need for more physiologically relevant models in fibrosis research.

4.1.3 Combined treatments

In a 3-year, two-phase randomized controlled trial involving 168 patients, (Cai et al., 2023), demonstrated that Hydronidone combined with ETV significantly improved liver fibrosis associated with chronic hepatitis B, with 270 mg identified as the optimal dosage. (Salama et al., 2024). reported that combination therapy with Quercetin and Simvastatin was more effective than monotherapy in treating liver fibrosis, as evidenced by reduced expression of sphk1 and nlrp3 mRNA, indicating inhibition of the SphK1/NLRP3 signaling pathway. (Azizsoltani et al., 2023). explored mesenchymal stem cell-derived exosomes (MSC-ex) as a delivery platform for Obeticholic Acid (OCA), enhancing targeted delivery and mitigating side effects while effectively alleviating liver fibrosis in mouse models. Similarly, (Bai Y. et al., 2024), employed nanotechnology to improve Melatonin bioavailability, developing PM@PLGA and HSCM@PLGA nanoparticles that exhibited enhanced anti-fibrotic efficacy in animal models. (Xia et al., 2023). designed biomimetic nanoparticles (TM-ATRA/NPs) encapsulating all-trans retinoic acid (ATRA) within LX2 cell membrane-derived vesicles expressing TRAIL, which induced apoptosis and quiescence in activated hepatic stellate cells (HSCs), thereby ameliorating fibrosis in a mouse model. (Zhang Y. W. et al., 2023). developed HCQ@VA-Lip-Exo, a vitamin A-modified hybrid nanobiomimetic delivery system that effectively targeted activated HSCs, suppressed autophagy, and reduced extracellular matrix (ECM) synthesis and deposition. (Hou et al., 2024). further demonstrated that HCQ@ROL-LNPs selectively inhibited activated HSCs. (Tran et al., 2022). showed that sora@sirnp nanoparticles enhanced sorafenib bioavailability, producing anti-fibrotic effects while reducing gastrointestinal side effects. In another nanomedicine approach, a previous study identified silymarin-chitosan nanoparticles as a potent anti-fibrotic nanoformulation (Abdullah et al., 2022) that upregulated protective liver miRNAs and downregulated fibrosis-related markers such as TGFβR1, COL3A1, and TGFβR2. (Wang X. et al., 2024). developed HA@PRB/COL nanoparticles, a hyaluronic acid-based delivery system that targeted HSCs via CD44 receptors and facilitated ECM collagen I degradation through collagenases (COLs), effectively preventing HSC activation. Overall, combining conventional biomedicine medicines with MSC-ex or nanoparticles holds considerable promise for treating liver fibrosis by enhancing bioavailability, improving targeting, and reducing side effects. However, current studies often emphasize efficacy while overlooking adverse effects, limiting the comprehensiveness of research.

4.2 Potential molecules treatment for liver fibrosis

The evolving landscape of liver fibrosis research underscores the limitations of conventional biomedicine therapies in achieving cellular specificity. In response, there is growing interest in developing novel therapeutics based on protein and nucleic acid molecules (Table 3).

4.2.1 Protein molecules

(Zhang et al., 2022b) identified S100A16 as a suppressor of CXCR4 expression, which attenuated hepatic stellate cell activation by inhibiting the ERK1/2 and AKT signaling pathways. (Xu et al., 2022). demonstrated that silencing Igf2bp2 ameliorated fibrosis by modulating Tgfbr1 through the PI3K/Akt pathway. (Tong et al., 2022). revealed that FGF18 mitigates liver fibrosis via the SMO-LATS1-YAP signaling axis. Similarly, (Ning et al., 2023), showed that anti-PCSK9 antibodies reduce liver inflammation and fibrosis by modulating the AMPK/mTOR/ULK1 pathway and inhibiting hypoxia-induced hepatocyte autophagy. (Fondevila et al., 2022). reported that CPT1A silencing diminished mitochondrial activity, thereby suppressing HSC activation. (Guo et al., 2022). showed that knockdown of Mlkl specifically reduced hepatocyte necroptosis and HSC activation. (He et al., 2022). proposed that SNS-032, a cyclin-dependent kinase nine inhibitor, alleviates fibrosis by inducing apoptosis and suppressing activated HSCs. (Zhang K. et al., 2023). demonstrated that GPR65 knockout reduces hepatic inflammation and fibrosis through inhibition of the JNK and NF-κB pathways. Finally, (Wang L. et al., 2023), found that Sema4D knockdown downregulates AOX1 and RARA, thereby modulating T helper cell balance and counteracting liver fibrosis. (Li X. et al., 2023). demonstrated that GDF15 mitigates liver fibrosis progression by reprogramming macrophage metabolism to favor anti-inflammatory phenotypes. Similarly, (Isaac et al., 2024), highlighted the role of TM7SF3 in attenuating nonalcoholic steatohepatitis (NASH)-related liver fibrosis through regulation of the transcription factor TEAD1. (Grøndal et al., 2024). showed that Bemcentinib alleviates MASH-induced liver fibrosis by targeting AXL, thereby modulating the inflammatory responses of Kupffer cells and CD8⁺ T cells. In another study, (Kim et al., 2024), identified Galectin-3-binding protein as a potential biomarker for distinguishing stages of hepatic fibrosis and demonstrated its anti-fibrotic effects via modulation of the TGF-β1 signaling pathway. Additionally, (Li F. et al., 2023), investigated the effects of riociguat-pretreated IGNP-JQ1 on hepatic stellate cells (HSCs) in two murine models of liver fibrosis. Their findings revealed that this intervention significantly reduced hepatic fibrosis by enhancing substance exchange efficiency within liver tissue. Collectively, these studies have found that different molecular targets have intervening effects on liver fibrosis, but further exploration of their specific mechanisms of action is still needed.

4.2.2 Nucleic acid molecules

Nucleic acids, particularly small interfering RNA (siRNA) and microRNA (miRNA), play pivotal roles in regulating liver fibrosis by modulating gene expression and signaling pathways. These molecules have emerged as promising therapeutic agents capable of halting fibrosis progression through targeted gene silencing. (Lawitz et al., 2022). administered BMS-986263—an siRNA targeting HSP47 mRNA—to 61 HCV-SVR patients with advanced liver fibrosis, reporting improvements in both METAVIR and Ishak scores. Infusion-related reactions were the most common adverse events. (Markovic et al., 2024). observed significant reductions in miR-190b-5p and miR-296-3p levels in murine and human liver fibrosis models, identifying hyaluronan synthase 2 (HAS2) and integrin alpha-6 as novel therapeutic targets. (Zhao et al., 2019). provided a comprehensive review of siRNA- and miRNA-based strategies for liver fibrosis, elucidating their mechanisms and therapeutic potential. Beyond canonical nucleic acids, researchers are also investigating related biological processes. (Li X. J. et al., 2023). showed that H19-regulated EZH2 reprograms H3K27me3, activating HSCs, promoting epithelial–mesenchymal transition (EMT), and triggering Wnt/β-catenin signaling—suggesting that disrupting this interaction could represent a novel therapeutic strategy. (Zheng et al., 2022). found that uridine modulates hepatic cell activity, reducing collagen accumulation and downregulating the expression of α-SMA, type I collagen, and fibronectin. (Cheng et al., 2023). reported that mesenchymal stem cell (MSC)-derived exosomes alleviate hepatic fibrosis by delivering miR-27b-3p to inhibit the YAP/LOXL2 signaling axis. Similarly, (Tian et al., 2022), showed that MSC-derived exosomes transporting miR-148a modulate intrahepatic macrophage activity via the KLF6/STAT3 pathway, thereby reducing fibrosis. (Wang Y. et al., 2024). further demonstrated that MSC-derived small extracellular vesicles modulate LOXL2 to facilitate miR-4465 delivery into HSCs, contributing to anti-fibrotic effects. Several nanoparticle-based delivery platforms have also shown promise. (Shan et al., 2024). used retinoid-derived lipid nanoparticles (LNPs) to deliver therapeutic protein mRNA in three NASH-associated liver fibrosis models, achieving enhanced protein retention and reduced systemic toxicity. (Han et al., 2023). developed AA-lipid-like LNPs that improved RNA delivery efficiency to activated fibroblasts and exhibited superior transmission compared to conventional LNPs. (Jeong et al., 2024). demonstrated that engineered LNPs delivering siGTSE1 to hepatocytes significantly reduced collagen accumulation. In a related study, (Zhang C. et al., 2023), observed IL-1β upregulation in two mature NASH mouse models and showed that siRNA-loaded nanoparticles targeting the IL-1β/ERK pathway effectively inhibited HSC activation and attenuated fibrosis. By targeting specific genes, nucleic acid molecules can regulate gene expression and signaling pathways, and achieve precise gene silencing. Not only do they improve symptoms, but they may also slow or even reverse the fibrosis process. However, the full mechanism of their role in disease progression needs to be further explored.

5 Botanical drug metabolites treatment for liver fibrosis

In medicinal research, clinical observations and empirical findings are fundamental to drug development. Botanical drugs has accumulated extensive clinical experience in managing liver fibrosis, offering a valuable foundation for pharmacological investigations. This body of knowledge suggests that specific botanical drug metabolites may hold therapeutic potential against hepatic fibrosis. Numerous reviews have explored phytotherapeutic strategies for hepatic fibrosis, often emphasizing key botanical drug metabolites such as polyphenols, phenolic acids, and flavonoids, along with their underlying mechanisms of action (Wenbo et al., 2024; Zhao B. et al., 2024). To advance this field, a phenotypic perspective on hepatic fibrosis—alongside a synthesis of recent mechanistic insights—may offer new avenues for therapeutic exploration. Table 4 presents a summary of studies investigating botanical drug metabolites in the treatment of hepatic fibrosis, with plant species cross-referenced against the MPNS database (https://powo.science.kew.org/).

5.1 Effects of botanical drug metabolites on the phenotype or mechanism of liver fibrosis

Aloin has demonstrated anti-fibrotic effects by inhibiting hepatic stellate cell (HSC) activation and attenuating CCL4-and TGF-β1-induced inflammatory responses in both in vitro and in vivo models (Bai et al., 2023). Activated HSCs contribute to fibrosis by promoting apoptosis, extracellular matrix (ECM) accumulation, and hepatocyte pyroptosis. (Wan et al., 2023). reported that the total polyphenolic glycosides of Lamiophlomis rotata suppress HSC proliferation via inhibition of the TGF-β/Smad pathway and enhance apoptosis of activated HSCs, thereby ameliorating liver fibrosis. Similarly, Gypenosides were shown to inhibit TGF-β-induced HSC activation and reduce ECM deposition, leading to fibrosis attenuation in vivo (Li et al., 2023b; Yong et al., 2024) found that Gentiopicroside (GPS), derived from Gentiana scabra Bunge, inhibits HSC activation by blocking the TLR4 and NLRP3 signaling pathways and suppressing hepatocyte pyroptosis. In a related study, (Luo et al., 2022), demonstrated that Celastrol alleviates hepatic fibrosis by inducing ferroptosis in activated HSCs through modulation of peroxiredoxins and heme oxygenase-1 (HO-1).

Emerging evidence suggests that botanical drug metabolites often target multiple fibrotic phenotypes simultaneously. For instance, (Chen et al., 2023), reported that Ganoderma lucidum polysaccharide (GLP) attenuates hepatic fibrosis by regulating inflammation, cell cycle progression, apoptosis, and ECM-receptor interactions. In another study, (Chen et al., 2022), showed that demethylzeylasteral inhibits HSC proliferation, migration, and activation, and downregulates fibrogenic gene expression by suppressing FAK and AKT phosphorylation through inhibition of the AGAP2-mediated signaling pathway.

Botanical metabolites also exert anti-fibrotic effects by reducing oxidative stress and inflammation driven by activated HSCs. Notoginsenoside R1, a metabolite of Panax notoginseng, alleviates fibrosis by suppressing HSC activation and downregulating NF-κB and MAPK signaling pathways, thereby exerting both antioxidant and anti-inflammatory effects (Gong et al., 2022). Some studies have extended beyond HSC-focused mechanisms. For example, CXAL and CXPHL, metabolites of Chuanxiong Rhizoma, mitigate hepatic fibrosis by modulating the CTCF–c-MYC–H19 pathway and reducing HSC-mediated collagen contraction (Li Y. et al., 2024). Additionally, (Liu Y. et al., 2023), demonstrated that Paeoniflorin exerts anti-fibrotic effects by modulating macrophage polarization via the NF-κB/HIF-1α signaling pathway.

This study also revealed novel mechanisms involved in the pathogenesis and mitigation of liver fibrosis. Triterpenoids have been shown to attenuate hepatic fibrosis by modulating NF-κB and TGF-β1/Smads signaling pathways, as well as by increasing the abundance of the gut microbiota genus Ruminococcus (Zhang J. et al., 2024). Similarly, Kuhuang alleviates liver fibrosis by influencing the gut microbiota’s regulation of hepatic interferon signaling and bile acid metabolism (Shen B. et al., 2022; Li Z. et al., 2024) reported that Cryptotanshinone (CTS) was reported to reduce liver fibrosis through the inhibition of p-STAT3/CPT1A-mediated fatty acid oxidation. (Jiang S. et al., 2023). showed that Triptolide exerts its anti-fibrotic effects by modulating T-helper (Th) and CD4⁺ T cell differentiation. According to (Li et al., 2022), Didymin, a metabolite derived from Origanum vulgare L., primarily mitigates hepatic fibrosis by reducing endoplasmic reticulum stress and altering glycerophospholipid metabolism. In addition to small-molecule metabolites, several protein-related mechanisms have emerged as promising anti-fibrotic targets. Glabridin alleviates inflammation and oxidative stress via PPARγ activation, thereby suppressing fibrotic progression (Zhang L. et al., 2022; Zhang L. et al., 2024) demonstrated that Astragalus saponins, through activation of the FXR receptor, downregulate key proteins implicated in hepatic fibrosis, particularly in cholestatic liver disease models. Isoliquiritigenin (ISL) inhibits ANXA2 expression and blocks the sphks/S1P/IL-17 signaling axis while suppressing STAT3 phosphorylation, leading to reduced α-SMA expression and fibrosis reversal (Liu N. et al., 2023). The investigation of botanical drug metabolites has expanded rapidly in recent years (Dan et al., 2024). However, focusing solely on mechanistic studies is insufficient to address clinical demands. If botanical drug metabolites that can act on the initial causes of primary liver diseases and effectively target liver fibrosis are successfully developed, for example, identifying botanical drug metabolites capable of simultaneously ameliorating cholestasis and liver fibrosis would substantially enhance research significance and translational potential. Mirroring the successful development trajectories of artemisinin and tanshinone, such efforts are critical to advancing liver fibrosis treatment. In contrast, existing agents such as colchicine, lificigat, and 4PBA lack fibrosis-specific efficacy, have limited clinical validation, and show weak mechanistic alignment, rendering them suboptimal as positive control drugs in experimental models.

5.2 Combined application

Combination strategies have demonstrated enhanced therapeutic efficacy. (Elzoheiry et al., 2022). addressed curcumin’s poor bioavailability using green silver nanoparticles (AgNPs) for targeted delivery in a mouse model, which resulted in significantly reduced liver fibrosis severity. (Dong H. et al., 2023). developed a multifunctional nanosystem (MnO₂@PLGA/Ssb1), which integrates MnO₂ with saikosaponin b1 (Ssb1) to augment its anti-fibrotic activity by scavenging excess H₂O₂ and relieving hypoxic stress. (Tang et al., 2023). utilized mesoporous polydopamine (MPO) for targeted drug delivery in both animal and cell models. MPO effectively reduced hepatic reactive oxygen species (ROS) and modulated the TGF-β/Smad signaling pathway, thereby attenuating fibrosis. Encapsulation of oxymatrine in MPO further enhanced therapeutic efficacy by restoring TGF-β/Smad signaling balance and reducing fibrotic progression. Similarly, (Ashour et al., 2021), demonstrated that lipid nanocapsules encapsulating Tanshinone IIA (TSIIA-LNCs) exerted superior anti-fibrotic effects compared to the free compound. (Gong et al., 2023). employed milk-derived exosomes modified with hyaluronic acid (HA-mExo-FA) to deliver Forsythiaside A. This nanocomplex targeted CD44 receptors on activated hepatic stellate cells, significantly inhibiting TGF-β1-induced LX2 cell proliferation, downregulating α-SMA expression, and promoting apoptosis (Meng et al., 2024). We found that many studies have been carried out on the combined application of mesenchymal stem cell exosomes (MSC-ex) or nanoparticle-based systems with botanical drug metabolites, potential molecules, and biomedicine medicines, however, there is still a lack of systematic comparative studies on the therapeutic effects of MSC-ex, nanoparticle-based systems and these medicines in the treatment of liver fibrosis. In the future, it is of great significance to carry out relevant comparative research.

6 Traditional Chinese medicine formulas treatment for liver fibrosis

Liver fibrosis, as a chronic progressive condition, has long been managed using TCM formulas, many of which are clinically validated. Increasingly, clinical studies are evaluating the integrative potential of TCM and biomedicine medicines in treating liver fibrosis. The TCM literature extensively documents the therapeutic efficacy of classical and empirically derived formulas. Recent rigorous investigations have elucidated the molecular mechanisms underlying these TCM-based interventions (see Table 5), further validating their relevance in modern hepatology.

6.1 The “guidelines for diagnosis and treatment of hepatic fibrosis with integrated traditional Chinese and Western medicine (2019 edition)”

(Xu and Liu, 2020) highlighted several patented TCM formulas with demonstrated efficacy. In a single-arm clinical trial using objective performance criteria, 251 patients with chronic hepatitis B (CHB) and advanced liver fibrosis underwent 48 weeks of combined therapy with Fuzheng Huayu (FZHY) tablets and entecavir (ETV). The FZHY group showed a significantly higher rate of fibrosis improvement—15% greater than with ETV monotherapy (Zhao et al., 2022). A comprehensive review (Zhou et al., 2024) concluded that FZHY is broadly applicable for treating liver fibrosis across various chronic liver diseases, with numerous animal and cellular studies confirming its effectiveness in targeting all known pathogenic mechanisms of fibrosis. (Dai et al., 2023). reported that Liver Qi Stagnation and Spleen Deficiency Syndrome were the predominant TCM syndromes among patients treated with FZHY. In a study of 400 CHB patients (Liu Y. Q. et al., 2023), compared ETV monotherapy with a combination of ETV and Anluohua Xianwan (ALHX), finding a significantly higher rate of fibrosis regression in the combination group. Similarly, a randomized controlled trial involving 270 CHB patients with early-stage liver fibrosis demonstrated that 48 weeks of Anluo Huaxian Pills (AHP) significantly improved fibrosis compared to placebo, with no notable adverse effects observed in the AHP group (Xiao et al., 2022). In another multicenter, randomized, double-blind, placebo-controlled trial, (Rong et al., 2022), showed that 72 weeks of ETV combined with Biejia-Ruangan (BR) significantly enhanced fibrosis regression in 500 patients with advanced CHB-related liver fibrosis. Preclinical studies support these findings. In rat models, Ganshuang Granules (GSG) reduced key fibrosis biomarkers, and in vitro studies indicated that its active compound, Naringin, may attenuate fibrosis by modulating the TGF-β/Smad signaling pathway (Wang F. et al., 2024). Although FZHY has been extensively studied-particularly in patients with Liver Qi Stagnation and Spleen Deficiency-the international persuasiveness of this evidence remains limited. Future research should focus on improving trial design and further exploring TCM syndrome differentiation to strengthen the global acceptance and methodological rigor of related studies. Meanwhile, clinical research on other formulas such as GSG and Biejia-Ruangan remains scarce, with even fewer studies elucidating their mechanisms of action.

6.2 Integration of other TCM formulas with biomedicine medicines for liver fibrosis

(Xing et al., 2023) evaluated 240 patients with advanced CHB-related fibrosis and found that 48 weeks of combination therapy with ETV and Ruangan Granule (RG) significantly reduced fibrosis severity. In a retrospective study, (Yu and Ge, 2024), reported that Bushen Huayu Decoction combined with ETV produced greater reductions in fibrosis markers than ETV alone, with statistically significant improvements observed at both 2 and 4 weeks. (Bi et al., 2023), including 22 randomized controlled trials, showed that commercial Chinese polyherbal preparation (CCPP) combined with ursodeoxycholic acid (UDCA) was more effective for primary biliary cholangitis (PBC)-related fibrosis than either treatment alone. In the future, more high-quality clinical studies can be carried out to further verify the efficacy of integrated traditional Chinese and biomedicine medicines, and provide patients with more effective treatment options.

6.3 Classic TCM formulas

Mechanistic studies continue to advance understanding of TCM therapies. (He et al., 2024). found that Dahuang Zhechong pills ameliorate liver fibrosis by modulating gut microbiota and associated metabolites. (Huang et al., 2023). demonstrated that Jiawei Taohe Chengqi Decoction inhibits HSC activation via the Src/ERK/Smad3 signaling pathway. (Ye et al., 2024). further showed that this decoction mitigates fibrosis by targeting activated HSCs through both the TGF-β1/CUGBP1 and IFN-γ/Smad7 pathways. In addition, (Shao et al., 2024), revealed that the same decoction suppresses HSC activation via inhibition of the Notch signaling pathway and modulation of macrophage polarization. The Guizhifuling Pill exhibits hepatoprotective effects by regulating the Nrf2/HO-1 antioxidant axis and inhibiting the NF-κB inflammatory signaling pathways (Baogui et al., 2022), as well as modulating the PTEN/AKT/mTOR signaling pathway (Yao et al., 2024; Wu et al., 2024) demonstrated that Tao-Hong-Si-Wu-Tang attenuates liver fibrosis by restoring lipid metabolism, inhibiting long-chain acyl-CoA synthetase 4 (ACSL4), and promoting mitophagy. Similarly, (Qu et al., 2024), reported that Si-Wu-Tang reduces ECM deposition and liver fibrosis through the H19-associated miRNA pathway. (Wang S. J. et al., 2023). reported that Xiaochaihu Tang alleviates hepatic fibrosis through leptin and Nrf2 signaling pathways. (Jiang M. et al., 2023). showed that Isorhamnetin, a key metabolite of Sini San, prevents the AKT-mediated suppression of FXR expression. (Zhao Y. et al., 2024). that Danggui Shaoyao San ameliorates hepatic fibrosis by modulating gut microbiota and their metabolites, particularly short-chain fatty acids (SCFAs) and bile acids (BAs). Classic TCM formulas have been extensively studied and applied to a variety of diseases, and their best indications are not limited to liver fibrosis. In the future, clinical studies need to be strengthened to better determine its optimal application in the treatment of liver fibrosis.

6.4 Hospital-based TCM empirical formulas

The Qijia Rougan formula exerts anti-fibrotic effects by regulating the JAK1/STAT6/microRNA-23a axis through M2 macrophage polarization (Zheng Y. et al., 2023). The Tianhuang formula reduces liver fibrosis by targeting the CCL2/CCR2 axis and downregulating the MAPK-NF-κB pathway (Lan et al., 2024). Yangyinghuoxue decoction mitigates fibrosis via PI3K/Akt pathway activation (Bai Y. M. et al., 2024). Qiwei Tiexie capsule effectively combats hepatic fibrosis by suppressing NLRP3 inflammasome activation while enhancing hydroxyproline content and glutathione peroxidase activity in vivo (Wang S. et al., 2024). Gentiana decoction, as reported by (Deng et al., 2024), inhibits HSC activation through the Parkin signaling pathway. The Danhongqing formula exhibits anti-fibrotic activity by downregulating long non-coding RNA H19, promoting LX-2 cell apoptosis, and inhibiting HSC activation (Li M. et al., 2024; Xue et al., 2024) showed that the Ba-Qi-Rougan formula suppresses activated HSCs via the CCR2/PI3K/AKT signaling pathway. Wuling capsules activate the NF-κB signaling cascade, a critical regulator of inflammation and immunity, thereby reducing hepatic fibrosis (Ren et al., 2024). Ganfule capsules inhibit glutamine metabolism linked to NF-κB signaling, contributing to anti-fibrotic effects (Ke et al., 2022). Fufang Muji granules improve hepatic fibrosis by modulating the TGF-β1/Smad pathway, inhibiting apoptosis, regulating metabolism, and alleviating oxidative stress and inflammation (Men et al., 2024). The Yi-Qi-Jian-Pi formula reverses liver fibrosis by inhibiting the TGF-β/Smad3 axis and modulating the abundance of Calditerrivibrio nitroreducens, which negatively correlates with 18β-glycyrrhetinic acid (Yang et al., 2024). Huangqi Decoction exerts anti-fibrotic effects by regulating the lnc-C18orf26-1/miR-663a/TGF-β axis (Dong B. S. et al., 2023).

Currently, the majority of PubMed-indexed studies on TCM formulas are experimental, focusing primarily on elucidating molecular mechanisms. These findings underscore a pressing need for the global research community to clarify the mechanisms of action of TCM formulas through robust scientific inquiry formulas. Future efforts should prioritize rigorous clinical trials to validate these formulas and improve their scientific credibility and global acceptance. Furthermore, formulas derived from botanical drug metabolites may offer enhanced therapeutic efficacy compared to traditional TCM formulas. As such, expanding clinical trials to evaluate both metabolite-based formulas is of substantial significance.

7 Discussion

Liver fibrosis, a common manifestation of chronic liver diseases, remains a major clinical challenge due to the absence of targeted anti-fibrotic therapies. The diversity of potential therapeutic agents highlights the urgent need for continued research. This review systematically compiles clinical and experimental studies and demonstrates the efficacy of various treatment medicines.

8 Conclusion

This review provides a comprehensive analysis of the pathological mechanisms underlying liver fibrosis, systematically sorts out various therapeutic medicines, and analyzes its research status. However, there are some gaps in existing studies, which can easily lead to one-sided research results and affect the comprehensive grasp of the treatment of liver fibrosis. Moreover, there is a critical need to expand the scale and depth of clinical trials, continuously refine liver fibrosis models, and work toward greater standardization and normalization in pharmacological research. These efforts will collectively accelerate the development of effective, targeted treatments for liver fibrosis.

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