Chuyue Zhang1
Lijun Shi- 1Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- 2Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
Non-alcoholic fatty liver disease (NAFLD) is characterized by core pathological features such as hepatic lipid accumulation, oxidative stress, and inflammatory responses. Its pathogenesis is closely associated with dysregulated energy metabolism. Adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cellular energy homeostasis, ameliorates NAFLD-related lipid metabolic imbalance and liver injury by phosphorylating downstream target proteins (e.g., ACC, mTOR, SREBP-1c). This process suppresses fatty acid synthesis, promotes oxidative degradation, inhibits inflammasome activation, and enhances antioxidant capacity. Recent studies have identified reduced AMPK activity as a critical pathological hallmark of NAFLD. Targeted activation of the AMPK signaling pathway alleviates NAFLD progression through multiple mechanisms, including lipid metabolism regulation, anti-inflammatory effects, restoration of antioxidant capacity, and enhanced autophagy. Natural products derived from traditional Chinese medicine have shown significant potential in regulating the AMPK signaling pathway. Research indicates that Traditional Chinese Medicine (TCM) extracts (e.g., terpenoids, phenols, flavonoids, saponins, and alkaloids) can directly activate AMPK or regulate its upstream kinases (LKB1, CaMKKβ) and downstream effectors (SIRT1, PPARα, Nrf2), thereby improving hepatic lipid accumulation, mitigating inflammatory damage, and delaying NAFLD progression. By searching the databases of Web of Science, PubMed, Google Scholar and CNKI, and integrating the latest research progress, systematically summarizes the role of the AMPK pathway in NAFLD and the intervention mechanisms of natural products, aiming to provide a theoretical basis for the development of innovative traditional Chinese medicine drugs for NAFLD.
1 Introduction
Non-alcoholic fatty liver disease (NAFLD) has evolved into a global epidemic, currently affecting approximately 30% of the adult population worldwide—equating to over two billion individuals—and its prevalence continues to rise in parallel with the global surge in obesity and type 2 diabetes (T2DM) (Powell et al., 2021). As the leading cause of chronic liver disease globally, NAFLD imposes a substantial public health burden, contributing significantly to liver-related morbidity, mortality, and healthcare costs (Nassir, 2022). Clinically defined by excessive hepatic lipid accumulation in the absence of excessive alcohol intake or other secondary causes of liver injury, NAFLD exhibits a strong bidirectional association with metabolic syndrome: up to 75% of adults with cardiometabolic conditions (e.g., obesity, T2DM, dyslipidemia) develop NAFLD, while NAFLD itself exacerbates systemic metabolic dysfunction (Steinberg et al., 2025).
Reflecting advances in understanding its pathogenesis, the nomenclature of this condition has undergone critical revisions. In 2020, an expert panel proposed renaming NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) to emphasize its metabolic roots and heterogeneous presentation, including potential coexistence with other liver diseases (Eslam et al., 2020). Despite partial international adoption, concerns arose regarding ambiguities in etiological characterization and the stigmatizing connotation of the term “fatty” (Lonardo et al., 2024). To address these issues, a 2023 multi-society Delphi consensus further revised the nomenclature to metabolic dysfunction-associated steatotic liver disease (MASLD), the currently accepted terminology (Rinella et al., 2023).
Despite its clinical significance, therapeutic options for NAFLD remain limited. While Resmetirom, a thyroid hormone receptor-β agonist, received FDA approval in 2024 for treating non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate-to-severe fibrosis, its application is restricted to specific patient subsets, leaving a substantial treatment gap for early-stage disease and broader patient populations (Harrison et al., 2024). Additionally, conventional synthetic agents often carry risks of adverse effects with long-term use, underscoring the need for safer, more accessible therapeutic alternatives.
In this context, the AMPK signaling pathway has emerged as a pivotal therapeutic target (Palomer et al., 2025). As a conserved energy sensor, AMPK regulates key biological processes including glucose/lipid metabolism, inflammation, and autophagy by responding to cellular energy status (via AMP/ATP ratios) (Steinberg and Hardie, 2023; Marcondes-de-Castro et al., 2023). Dysregulated AMPK activity—characterized by reduced phosphorylation—is a hallmark of NAFLD pathogenesis, driving excessive de novo lipogenesis, impaired fatty acid oxidation, inflammasome activation, and mitochondrial dysfunction, all of which exacerbate hepatic steatosis and injury (He et al., 2024; Lv et al., 2024; Liu et al., 2023). Restoring AMPK function thus represents a core strategy for NAFLD intervention.
Notably, bioactive metabolites derived from TCM have gained attention for their ability to modulate AMPK-mediated pathways. Through multi-metabolite synergies, these natural products target key axes such as AMPK/SREBP-1c (lipid synthesis) and AMPK/mTOR (autophagy), coordinately regulating lipid homeostasis and mitigating hepatic injury (Cheng et al., 2023; Zhang LJ. et al., 2025). This review systematically synthesizes the mechanistic role of AMPK in NAFLD pathogenesis and the regulatory effects of TCM-derived natural products, aiming to provide a theoretical framework for developing novel therapeutics (Figure 1).
Figure 1. Sketch of natural products intervening in non-alcoholic fatty liver disease.
2 Methods and literature search strategy
To investigate the mechanism by which natural product interventions exert therapeutic effects on NAFLD through the AMPK signaling pathway.The electronic databases PubMed, Web of Science, Google Scholar and CNKI database were searched from their inception until 2025. The search strategy combined keywords and Medical Subject Headings (MeSH) terms related to: (1) Intervention: (“traditional Chinese medicine” OR “Chinese herbal medicine” OR “natural product” AND (2) Disease: (“NAFLD”). Inclusion criteria were: (1) in vitro or in vivo studies; (2) studies investigating defined TCM metabolites or chemically characterized extracts; (3) studies reporting outcomes related to AMPK mechanisms (e.g., egulating lipid metabolism, inhibiting inflammatory responses, alleviating oxidative stress and regulating autophagy). Exclusion criteria were: (1) reviews, editorials, or conference abstracts; (2) studies using undefined crude mixtures (Figure 2).
Figure 2. Flow diagram.
In addition, literature should be excluded that includes “pan assay interfering metabolites”. Readers may consult the original publications for precise statistical tests and exact p-value thresholds via the hyperlinked references.
All herbal medicines derived from plants have undergone taxonomic verification (http://mpns.kew.org/mpns-portal/) and include complete species names (including authoritative nomenclature and taxonomic classification). As the MPNS covers only plant-derived medicines, any medicines derived from fungal or animal are referred to by their standard names throughout this article.
3 Activation and conduction of the AMPK signaling pathway
In mammals, AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase composed of three subunits: α, β, and γ. Among these, the α subunit serves as the catalytic subunit, while the β and γ subunits function as regulatory subunits (Smiles et al., 2024). AMPK regulates cellular energy metabolism and maintains energy homeostasis by sensing changes in the intracellular AMP/ATP ratio.
Activation of AMPK primarily depends on the phosphorylation of threonine 172 (Thr172) in the α subunit by upstream kinases, including liver kinase B1 (LKB1) and calcium/calmodulin-dependent protein kinase β (CaMKKβ) (Xie et al., 2022). Under conditions of energy deficiency, LKB1 translocates from the nucleus to the cytoplasm, where it forms a complex with accessory proteins (STRAD and MO25) and continuously phosphorylates AMPKα at Thr172, thereby triggering its kinase activity. While LKB1 activation is independent of changes in the AMP/ATP ratio, it is regulated by energy stress signals. Notably, during endoplasmic reticulum (ER) stress, CaMKKβ becomes activated and directly phosphorylates AMPKα-Thr172. This pathway operates independently of metabolic regulation but is particularly responsive to fluctuations in intracellular Ca2+ levels and signaling.
When cellular energy levels are sufficient, Thr172 in the α subunit remains unphosphorylated, and AMPK exists in an inactive form. However, when energy metabolism is impaired, AMP binds to the γ subunit of AMPK, inducing a conformational change that exposes Thr172, thus facilitating its phosphorylation by either LKB1 or CaMKKβ. This process is mediated through the nucleotide-binding pocket within the γ subunit, where AMP competitively inhibits ATP binding and enhances kinase activity (Trefts and Shaw, 2021).
Through phosphorylation of downstream target proteins, AMPK establishes a multidimensional regulatory network that coordinates energy metabolism and cellular homeostasis. These effects can be broadly categorized into three functional pathways: regulation of lipid synthesis, oxidative stress, and inflammatory responses.
1. AMPK phosphorylates acetyl-CoA carboxylase (ACC) at serine 79 (Ser79), inhibiting its catalytic activity. This leads to reduced production of malonyl-CoA and consequently relieves the inhibition of carnitine palmitoyltransferase 1 (CPT1), promoting fatty acid β-oxidation. Simultaneously, AMPK suppresses the nuclear translocation of sterol regulatory element-binding protein 1c (SREBP1c), downregulating the expression of key lipogenic enzymes such as fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), thereby inhibiting de novo triglyceride (TG) synthesis.
2. AMPK directly phosphorylates and inhibits mammalian target of rapamycin (mTOR), thereby alleviating mTOR-mediated suppression of the autophagy-initiating complex ULK1. In parallel, AMPK activates ULK1 by phosphorylating it at Ser317 and Ser777, synergistically promoting both lipophagy and mitophagy, which accelerates lipid clearance and degradation of damaged organelles. Moreover, AMPK activates peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), enhancing mitochondrial biogenesis and fatty acid oxidation capacity. Additionally, AMPK induces nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), upregulating antioxidant enzymes such as glutathione peroxidase (GPX), thereby mitigating oxidative stress injury.
3. Beyond promoting autophagic flux to clear dysfunctional mitochondria, AMPK also reduces reactive oxygen species (ROS)-mediated activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, subsequently suppressing the release of proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). The coordinated actions of these targets help maintain hepatic lipid metabolic balance and prevent the progression of non-alcoholic fatty liver disease (NAFLD) toward inflammation and fibrosis (Muraleedharan and Dasgupta, 2022; Jie et al., 2022).
4 The mechanism of the AMPK signaling pathway in NAFLD
NAFLD is a metabolic disease characterized by lipid accumulation in the liver, oxidative stress and chronic inflammation. AMPK, as a core regulatory factor of cellular energy metabolism, plays a key role in the occurrence and development of NAFLD through multiple mechanisms such as regulating lipid metabolism, inhibiting inflammatory responses, alleviating oxidative stress and regulating autophagy. Studies have found that the reduction of AMPK activity is an important pathological feature of NAFLD, and targeted activation of the AMPK signaling pathway can significantly improve liver lipid metabolism disorders and related pathological injuries (Figure 3).
Figure 3. Sketch of AMPK signaling pathway mechanism.
4.1 Regulation of lipid metabolism: bidirectional regulation of dynamic balance
AMPK regulates the dynamic balance between fatty acid synthesis and oxidation by phosphorylating downstream targets. In terms of lipid synthesis, AMPK, on the one hand, inhibits the generation of Malonyl-CoA by phosphorylating the Ser79 site of ACC. The decrease in the level of malonyl-CoA (experimental data show a reduction of 60%–80%) directly eliminates the allosteric inhibition of CPT1. Significantly enhance the transport efficiency of long-chain fatty acids (such as palmitate esters) to mitochondria (Liao et al., 2023). On the other hand, AMPK upregulates the expression of Insig-2a by blocking the Ser372 site of SEBP-1C and hindering its binding to the Sec23/24 complex, anchoring the SEBP-SCAP complex to the endoplasmic reticulum. This process deacetylates histone H3K27 in the promoter regions of FASN and SCD1. It leads to a decrease in its mRNA expression level and reduces the synthesis of triglyceride (TG) and lipid-toxic intermediate products (Winarto et al., 2023). At the lipid decomposition level, AMPK collaboratively upregulates the expression of mitochondrial and peroxisome fatty acid oxidation-related genes such as carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1) by activating peroxisome proliferator-activated receptor α (PPARα) and its co-activator PGC-1α. Accelerate lipid clearance and reduce lipid droplet deposition in the liver.
4.2 Inhibition of inflammatory response: dual-target intervention from NF-κB to NLRP3
AMPK alleviates hepatic inflammation by inhibiting the nuclear factor-κB (NF-κB) and NLRP3 inflammasome pathways. On one hand, AMPK blocks NF-κB nuclear translocation and reduces the transcription and release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) by enhancing the stability of inhibitor of nuclear factor κB alpha (IκBα) (Wang et al., 2024a). On the other hand, AMPK activates selective autophagy (such as mitophagy), thereby eliminating ROS and mitochondrial DNA (mtDNA) released from damaged mitochondria. This prevents ROS-dependent assembly of the NLRP3 inflammasome and caspase-1–mediated cleavage of pro-IL-1β and pro-IL-18, blocking the amplification of inflammatory signaling. In addition, AMPK can attenuate the hepatic inflammatory microenvironment and slow the progression of fibrosis by inhibiting M1 polarization of macrophages and the activation of hepatic stellate cells (HSCs).
4.3 Alleviating oxidative stress: the synergistic effect of Nrf2 pathway and mitochondrial repair
AMPK enhances hepatic antioxidant capacity by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE pathway. The activated AMPK directly binds to Nrf2, facilitating its dissociation from Keap1 and subsequent nuclear translocation. This process upregulates the expression of antioxidant enzymes including glutathione peroxidase (GPX), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1), thereby enhancing cellular capacity to eliminate oxidative damage (Yao and Liu, 2022). Concurrently, AMPK promotes mitochondrial biogenesis and repairs electron transport chain (ETC) complex activity by upregulating PGC-1α and mitochondrial transcription factor A (TFAM), effectively reducing superoxide anion generation caused by electron leakage. Furthermore, AMPK suppresses reactive oxygen species (ROS) production at its source by inhibiting membrane assembly of NADPH oxidase (NOX) and reducing xanthine oxidase (XO) activity. This comprehensive antioxidant defense system collectively protects hepatocytes from oxidative stress-induced injury.
4.4 Regulating autophagy: from lipid droplet clearance to organelle quality control
AMPK dual-activates autophagy through ULK1-dependent and mTOR-independent pathways to maintain hepatocyte homeostasis. Under energy stress conditions, AMPK directly phosphorylates the autophagy-initiating factor ULK1 at serine residues 317 and 777, promoting autophagosome formation (Ren Q. et al., 2024). Meanwhile, AMPK alleviates the negative regulation of autophagy by inhibiting mTORC1-mediated phosphorylation of ULK1 at serine 757. In non-alcoholic fatty liver disease (NAFLD), AMPK activation induces ubiquitin-mediated degradation of PLIN2, a protein coating lipid droplets, thereby enhancing the fusion of lipid droplets with autophagosomes and accelerating lipid hydrolysis (lipophagy). Furthermore, AMPK activates FUNDC1-mediated mitophagy to remove dysfunctional mitochondria, interrupting the ROS-inflammatory vicious cycle and thus maintaining the efficiency of the organelle quality control system.
4.5 The interaction network of AMPK with other metabolic pathways
The functional roles of AMPK extend beyond its classical functions to dynamic interactions with other metabolic pathways. For instance, AMPK inhibits mTORC1 signaling through phosphorylation of TSC2, while simultaneously activating the deacetylase activity of sirtuin 1 (SIRT1), collectively regulating autophagy and energy metabolism. Its synergistic interaction with the FGF21 pathway enhances hepatic insulin sensitivity. Moreover, by modulating the production of gut microbiota-derived metabolites (such as butyrate), AMPK indirectly influences liver lipid metabolism. This multidimensional network of interactions positions AMPK as a central hub linking energy sensing, metabolic regulation, and inflammatory responses, offering multiple therapeutic targets for the precise intervention of NAFLD.
5 Natural products regulate the AMPK signaling pathway for the treatment of NAFLD
Natural products can significantly intervene in the pathological progression of NAFLD by targeting the AMPK signaling pathway. Specifically, these bioactive phytochemicals primarily include terpenoids, phenolic metabolites, flavonoids, flavonoid derivatives, lignans, steroidal saponins, alkaloids, and ester metabolites. Through multi-target mechanisms, these active metabolites either directly activate the α-catalytic subunit of AMPK (via phosphorylation at Thr172) or indirectly modulate upstream kinases (such as LKB1 and CaMKKβ), thereby influencing the expression and activity of downstream key effector molecules, including ACC, SREBP-1c, and PPARγ. Ultimately, they exert comprehensive effects such as regulating lipid metabolism, improving insulin resistance, suppressing oxidative stress, and mitigating inflammatory responses, effectively delaying the pathological progression of NAFLD to non-alcoholic steatohepatitis (NASH) and hepatic fibrosis (Table 1).
Table 1. Natural products regulate the AMPK signaling pathway for the treatment of NAFLD.
5.1 Terpenoids
Terpenoid metabolites primarily regulate the AMPK/SREBP1, AMPK/mTOR, and AMPK/SIRT1 pathways to treat NAFLD. Asperuloside (ASP), an active metabolite of Hedyotis diffusa, exhibits various pharmacological activities, including antitumor and anti-inflammatory effects (Lu et al., 2022). It activates the AMPK/SREBP-1c signaling pathway, reducing the protein expression of SREBP-1c and FAS, thereby decreasing hepatic lipid accumulation in NAFLD mice, suggesting its potential as a therapeutic candidate for NAFLD (Shen Q. et al., 2023). Additionally, in high-fat diet (HFD)-induced NAFLD model animals, significant increases in TG, TC, LDL-C, ALT, and AST levels were observed alongside prominent hepatic lipid droplet formation; however, intervention with sea buckthorn triterpenic acids extract (STE) lowered lipid levels and upregulated p-AMPK/AMPK, SREBP1, FAS, and ACC expression, indicating STE’s ability to activate the AMPK/SREBP1 pathway for NAFLD treatment (Ma QG. et al., 2023; Ren L. et al., 2024). Limonin, a tetracyclic triterpenoid primarily derived from citrus fruits, was found by Si-Wei Wang to competitively inhibit AMPK activity, thereby suppressing hepatic lipid accumulation and the transcriptional activity of SREBP1 and SREBP2 in NAFLD model mice (Wang SW. et al., 2022). Notably, britanin (Bri), a sesquiterpene lactone extracted from Inula japonica, also reduces AMPK phosphorylation, downregulates SREBP1c expression, and alleviates hepatic oxidative stress and apoptosis by decreasing Caspase3 expression and the Bax/Bcl2 ratio, thereby mitigating NAFLD (Dou et al., 2024). Corosolic acid (CA), known as “plant insulin,” is a major metabolite of Lagerstroemia speciosa leaves and exhibits antidiabetic, anti-obesity, anti-inflammatory, antihyperlipidemic, and antiviral properties (Zhao et al., 2021). By modulating the AMPK/SREBP1c pathway, CA reduces serum TG and TC levels in HFD-induced NAFLD mice while downregulating SREBP1c, FAS, and SCD1 gene expression to attenuate hepatic lipid deposition (Wang Z. et al., 2023). Patchouli alcohol (PA), a tricyclic sesquiterpene with anti-inflammatory and antitumor effects (Xu QQ. et al., 2023), was shown by Do Hyeon Pyun et al. to activate the AMPK/SIRT1 pathway, ameliorating lipid accumulation in palmitate-induced hepatocytes and suppressing hepatic steatosis in HFD-fed mice, thus improving NAFLD (Pyun et al., 2021). Furthermore, camphorquinone (CQ), synthesized efficiently via sequential bromination and oxidation of camphor (Maharajan and Cho, 2021), activates the SIRT1/LKB1/AMPK pathway, downregulating ChREBP mRNA while upregulating CES1 and CES2 expression and reducing pro-inflammatory cytokines (IL-1α, IL-6, IL-8), thereby alleviating FFA-induced hepatic steatosis and improving lipid metabolism in NAFLD (Maharajan et al., 2025). mTOR, a key downstream target of AMPK, promotes autophagy-mediated lipid degradation upon AMPK/mTOR pathway activation, contributing to NAFLD treatment. Geniposide (GEN), an iridoid glycoside isolated from Gardenia jasminoides fruits, exhibits neuroprotective, hepatoprotective, anti-inflammatory, antioxidant, and antitumor properties (Gao and Feng, 2022). Bingyu Shen demonstrated that GEN activates the AMPK/mTOR pathway, enhancing phosphorylation of ACC, AKT, AMPK, and GSK3β while elevating antioxidant factors (Nrf2, PPARα, PPARγ, HO-1) and suppressing PI3K, p-mTORC, and HMGB1 expression, thereby reducing lipid accumulation and inhibiting NAFLD progression (Shen et al., 2020). Sweroside (SOS), an iridoid metabolite from Swertia plants, possesses anti-inflammatory, antioxidant, and hypoglycemic effects (Ma X. et al., 2023) and alleviates NAFLD by activating the AMPK/mTOR pathway to induce autophagy and mitigate hepatic steatosis (Ding et al., 2023). Lactucopicrin, a sesquiterpene lactone from chicory roots, also activates AMPK/mTOR, reducing p-mTOR, ROS, TG, and intracellular lipid droplets while upregulating PGC1α expression, thereby improving FFA-induced lipid accumulation in HepG2 cells (Tan et al., 2024). Bergenin (BER), a glycoside derivative of trihydroxybenzoic acid, exhibits antioxidant, anti-inflammatory, and hepatoprotective activities (Salimo et al., 2023). BER inhibits SIRT1/NF-κB pathway activation, reduces inflammatory cytokine expression, enhances AMPK/Nrf2 signaling (upregulating AMPK, Nrf2, and HO-1). And suppresses lipogenic proteins (SREBP-1, FAS), thereby exerting hepatoprotective effects (Lian, 2022).
5.2 Phenols
Pterostilbene (PTE), a metabolite with antioxidant, anti-inflammatory, antimicrobial, and anti-neuroinflammatory bioactivities, is primarily derived from Pterocarpus plants and fruits such as blueberries and grapes (Kim et al., 2020). PTE reduces oxidative stress damage caused by excessive lipid accumulation in hepatocytes by phosphorylating AMPK and inhibiting ACC activity, thereby promoting fatty acid metabolism and degradation (Shen B. et al., 2023). Gallic acid (GA) not only activates the AMPK-ACC-PPARα axis to reduce lipid levels in HepG2 cells and hepatic lipid accumulation in NAFLD mice but also alleviates NAFLD by improving mitochondrial function and decreasing excessive mitochondrial ROS production (Bai et al., 2021; Zhang J. et al., 2023). Furthermore, GA enhances AMPK phosphorylation to suppress the SREBP-1/ACC/FASN cascade, ameliorating hepatic steatosis in fructose-fed mice (Lu et al., 2023). Salvianolic acid A (SAA), a phenolic acid isolated from the roots of Salvia miltiorrhiza, improves lipid metabolism and mitochondrial function by modulating the AMPK/IGFBP1 pathway, thereby inhibiting hepatic steatosis (Zhu et al., 2024). Adlay polyphenol (AP), a bioactive phenolic metaboliteextracted from Coix lacryma-jobi L., exhibits various pharmacological effects, including antioxidant, anti-inflammatory, hepatoprotective, and lipid-modulating activities. AP regulates the AMPK/SREBP1C/ACC pathway, downregulating the expression of SREBP1C, FAS, and ACC to improve glucose and lipid metabolism, reduce lipogenesis, and suppress NAFLD progression in mice (Ma et al., 2022). Zingerone, a natural non-toxic phenolic metabolite derived from ginger, possesses antioxidant, anti-inflammatory, and antihyperglycemic properties (Shamsabadi et al., 2023). Heitham M. Mohammed et al. found that zingerone prevents high-fat diet-induced hepatic lipid deposition, steatosis, and oxidative damage in rats by activating the AMPK/Nrf2 pathway while inhibiting SREBP1, SREBP2, and NF-κB p65 (Mohammed, 2022). Additionally, eugenol, the main volatile metabolite of clove essential oil, ameliorates hepatic steatosis by modulating the AMPK/mTOR pathway to suppress SREBP1 and its target genes, thereby reducing TG and NEFA levels, offering a potential therapeutic approach for NAFLD and related metabolic disorders (Piao et al., 2022).
5.3 Flavonoids
Quercetin (Que), a flavonoid metabolite, exhibits antioxidant, anti-inflammatory, and lipid-accumulation-reducing effects (Singh et al., 2021). Studies demonstrate that it improves NAFLD by activating the AMPK pathway to enhance the expression of mitophagy-related proteins such as ATG5, ATG12, LC3, PINK1, and Parkin (Cao et al., 2023), inhibiting fatty acid synthesis via the ACC1/AMPK/PP2A axis (Gnoni et al., 2022), or regulating the AMPK/MAPK/TNF-α and AMPK/ACC/CPT1α pathways to suppress inflammation and lipid accumulation (Fu et al., 2022). Notably, baicalein (BAL), a flavonoid extracted from the roots of Scutellaria baicalensis, also activates the AMPK pathway, upregulates PGC1α and PPARα expression while suppressing mSREBP1c and ChREBP, thereby enhancing fatty acid oxidation and protecting the liver from high-cholesterol diet (HCD)-induced injury (Xiao et al., 2021; Li P. et al., 2022). Icariin, another flavonoid with anti-inflammatory and immunomodulatory properties (Bi et al., 2022), has been shown by Wei Lin et al. to elevate the expression of CPT-1, p-ACC/ACC, and PGC-1α while reducing serum cholesterol and triglyceride levels in NAFLD model mice through the AMPKα1/PGC-1α/GLUT4 signaling pathway (Lin et al., 2021). Plantamajoside (PMS), a flavonoid derived from the fruit of Plantago asiatica L., mitigates hepatocyte damage caused by excessive lipid peroxidation by activating the AMPK/Nrf2 pathway, upregulating HO-1 expression, and downregulating SREBF1, PPARγ, and FABP1 protein levels (Xu H. et al., 2023; Wu JM. et al., 2023). Importantly, lipid accumulation not only induces oxidative stress but also exacerbates inflammation. Chrysin (CN), a flavonoid extracted from Passiflora caerulea L., ameliorates hepatic lipid metabolic disorders by activating AMPK and modulating lipid metabolism-related proteins (e.g., SREBP1-c and ACC), while also suppressing the NLRP3/Caspase1 pathway to reduce pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-17), thereby counteracting NAFLD (Mishra et al., 2021; Gao et al., 2023). Impaired autophagy, particularly lipophagy, leads to hepatic TG accumulation and steatosis. Daidzein (DAI), a soy isoflavone with anti-inflammatory and antioxidant effects, alleviates oxidative stress and hepatocyte apoptosis in concanavalin A-induced liver injury by activating the SIRT1/AMPK pathway, increasing LC3-positive expression and Beclin-1 and LC3-II/LC3-I protein levels, enhancing autophagy, regulating lipid metabolism, and reducing hepatocyte apoptosis in NAFLD rats (Li et al., 2021; Wu D. et al., 2023). Additionally, vine tea total flavonoids (TFs) activate the AMPK/mTOR pathway to induce autophagy and modulate lipid metabolism-related proteins in HFD-fed mice, reducing de novo lipogenesis and regulating glycerophospholipid metabolism. In vitro studies further confirm their ability to decrease lipid droplets and TG content in oleic acid (OA)-treated HepG2 and L-02 cells (Du et al., 2024; Wang et al., 2024b).
5.4 Lignans
Schisandrin B (Sch B), one of the most abundant and highly active dibenzocyclooctadiene derivatives extracted from Schisandra chinensis fruits, exhibits diverse biological activities including antioxidant, anti-inflammatory, neuroprotective, and lipid-lowering effects (Fang et al., 2025). Studies demonstrate that Sch B activates autophagy via the AMPK/mTOR pathway, reducing lipid droplet accumulation in free fatty acid (FFA)-treated HepG2 cells and mouse primary hepatocytes (MPH), thereby inhibiting hepatic steatosis, enhancing fatty acid oxidation (FAO), and preventing NAFLD (Yan et al., 2022). Schisanhenol (SAL), a lignan metabolite derived from schisandra, possesses anticancer, antioxidant, and hepatoprotective properties (Olas, 2023). Research by Bin Li reveals that SAL activates the AMPK pathway by suppressing miR-802, upregulating p-ACC, CPT-1, and PPARα protein expression while downregulating SREBP-1c, consequently reducing hepatic TG, TC, and LDL-C levels while increasing HDL-C in NAFLD mice, thus modulating lipid metabolism to exert protective effects against NAFLD (Li B. et al., 2024). Honokiol (HK), a natural metabolite isolated from Magnolia officinalis, exhibits antitumor, anti-inflammatory, antibacterial, and anti-obesity activities (Wang D. et al., 2022). A previous study found that HK activates SIRT3-AMPK-mediated autophagy (primarily targeting lipid droplets) to attenuate lipid accumulation while maintaining mitochondrial function and promoting lipolysis, thereby alleviating hepatocyte lipotoxicity and positioning itself as a potential therapeutic candidate for NAFLD (Liu J. et al., 2021).
5.5 Saponins
Panaxadiol saponin metabolite (PDS-C), a bioactive cmetabolite isolated from total ginseng saponins (Dai et al., 2022), significantly improves liver function, hepatic steatosis, and lipid profiles in NAFLD mice by activating HO1 through the AMPK/Nrf2 signaling pathway while inhibiting NFκB, thereby alleviating oxidative stress and inflammation to mitigate NAFLD (Mi et al., 2024). Ginsenoside Rg5 (Rg5), a minor ginsenoside synthesized during the steaming process of ginseng with diverse pharmacological effects including antitumor, anti-inflammatory, and neuroprotective properties (Liu MY. et al., 2021), reduces TG, TC, LDL-C, AST, ALT, and MDA levels while increasing SOD, CAT, and GSH-Px activities via the LKB1/AMPK/mTOR pathway, effectively ameliorating hepatic steatosis, dyslipidemia, oxidative stress, and liver injury in NAFLD mice (Shi et al., 2024). Another ginseng-derived metabolite, ginsenoside CK, diminishes lipid deposition in HepG2 cells, attenuates weight gain in fructose-fed mice, alleviates lipid accumulation in serum and liver tissues, and improves hepatic inflammation and injury (Zhang J. et al., 2022). Furthermore, ginsenoside CK exerts therapeutic effects against NAFLD both in vitro and in vivo by activating LKB1 and AMPK phosphorylation to modulate the expression of lipid synthesis- and metabolism-related factors. Saponins of tomato extract (STE), possessing potent free radical-scavenging capacity, have been shown to activate the AMPK signaling pathway, thereby suppressing downstream fatty acid synthesis-related proteins FAS and SCD1 to reduce fatty acid production and improve lipid metabolism, while simultaneously enhancing Nrf2 nuclear translocation to initiate transcription of antioxidant factors SOD and NQO1, ultimately mitigating XT301 high-fat diet-induced oxidative stress and hepatic oxidative damage. Experimental results demonstrate that STE administration may be considered a viable therapeutic option for NAFLD (Yang et al., 2023).
5.6 Alkaloids
Recent studies have demonstrated that various alkaloid metabolites exhibit significant therapeutic potential for NAFLD by targeting the AMPK signaling pathway and its downstream effectors. Liensinine (LIEN), as an isoquinoline alkaloid, activates the TAK1/AMPK pathway to reduce PA-induced lipid accumulation and ROS generation in hepatocyte models in vitro, while bidirectionally regulating lipid metabolism-related proteins in HFD-induced mice - downregulating FAS, SCD, and PPARγ while upregulating PPARα, UCP2, and CPT-1α (Zhang W. et al., 2023; Liang et al., 2022). Similarly, Leonurine activates the ADRA1a/AMPK/SCD1 pathway through AMPKα and Thr172 phosphorylation, significantly decreasing hepatic SCD1 expression and reducing GPs and FFAs levels (Liu et al., 2024; Fan et al., 2024). Other alkaloids also demonstrate multi-target regulatory properties: Betaine coordinately inhibits SREBF1/ACC/FASN and activates LXR/SIRT1/PPARγ through the FGF10/AMPK pathway (Chen et al., 2021); Corydalis saxicola Bunting total alkaloids (CSBTA) suppresses the transcription of lipogenic genes (SREBF1, ACC1, and FASN) via the AMPK-SREBP1 axis (Guo et al., 2022; Guo et al., 2024); while berbamine (BBM) reduces ACC/FAS/SCD1 expression and decreases hepatic TG and TC content by approximately 50% through the SIRT1/LKB1/AMPK pathway (Farooqi et al., 2022; Sharma et al., 2021). Furthermore, oxymatrine (OMT) enhances SIRT1/AMPK/PPARα signaling and ACOX1/CPT1A expression, resulting in a 58% reduction of hepatic lipid accumulation in both in vivo and in vitro models (Li et al., 2023; Wu et al., 2025). These findings collectively indicate that alkaloid metabolites target the central node of the AMPK pathway, providing a multi-target intervention strategy for NAFLD treatment through a dual mechanism of inhibiting lipogenesis while promoting fatty acid oxidation.
5.7 Esters
Recent studies have demonstrated that terpenoids and phenolic metabolites exhibit multi-target therapeutic potential in the treatment of non-alcoholic fatty liver disease (NAFLD) by modulating the AMPK signaling pathway. Triptolide, for instance, significantly ameliorates NAFLD through a dual regulatory mechanism: on one hand, it enhances the phosphorylation of AMPK and ACC1 (increased by 2.1-fold and 1.8-fold, respectively), thereby suppressing key lipogenic factors such as SREBP-1 (↓42%) and SCD-1 (↓39%). On the other hand, it upregulates the expression of PPARα and CPT-1α (1.7–2.3-fold), promoting fatty acid β-oxidation (Gao et al., 2021; Huang et al., 2021). Similarly, Atractylenolide III (5–10 μM) reduces hepatic lipid accumulation by activating the AMPK/SIRT1 axis (by 35%–48%) and improves insulin sensitivity (Liu X. et al., 2022; Li Q. et al., 2022). Epigallocatechin gallate (50 mg/kg/day) also exerts multiple beneficial effects via the FGF21-AMPK pathway, including downregulation of lipogenic genes (e.g., SREBP-1c, 40%–55%), reduction of hepatic lipid droplet accumulation, and enhancement of antioxidant capacity (Bakun et al., 2023; Zhang Y. et al., 2022). Collectively, these metabolites converge on AMPK as a central regulatory node and exert synergistic effects through the mechanism of “inhibiting lipogenesis–promoting fatty acid oxidation–alleviating oxidative stress”, offering novel therapeutic strategies for NAFLD.
5.8 Flavonoids
Flavonoids, as natural modulators of the AMPK pathway, demonstrate remarkable multi-target therapeutic potential in NAFLD treatment. Cutting-edge research has revealed that these phytochemicals exert synergistic therapeutic effects by precisely regulating AMPK signaling networks across three critical pathological aspects: metabolic dysregulation, inflammatory response, and oxidative stress. Notably, mangiferin exhibits a unique dual mechanism, not only significantly elevating p-AMPKα expression levels but also innovatively targeting NLRP3 inflammasome activation, achieving marked reduction in hepatic lipid deposition (Xiang et al., 2024; Yong et al., 2021). More strikingly, hesperidin, Isoquercitrin and ugonin J demonstrate additional therapeutic value by improving insulin secretion and glycemic control through their respective dual-pathway modulation of AMPK/SREBP-1C and AMPK/AKT signaling (Ortiz et al., 2022; Chen et al., 2022; Chang et al., 2021; Kim et al., 2023). Particularly groundbreaking is the discovery of xanthohumol, which simultaneously inhibits lipogenesis and enhances antioxidant defenses (increased SOD and CAT activity) via AMPK/Nrf2 axis activation, offering novel perspectives for comprehensive NAFLD management (Atteia et al., 2023). These paradigm-shifting findings not only validate the multidimensional therapeutic advantages of flavonoids but also elucidate the central role of the AMPK pathway as a critical hub integrating metabolic-inflammatory-oxidative stress cross-regulation, thereby establishing a solid theoretical foundation for developing innovative natural product-based therapies for NAFLD.
5.9 Polysaccharide
Polysaccharide metabolites, serving as natural activators of the AMPK pathway, demonstrate unique “multi-target and multi-pathway” synergistic regulatory advantages in NAFLD treatment, enabling precise therapeutic intervention. Breakthrough studies reveal that fucoxanthin (FX) establishes an AMPK/Nrf2/TLR4 tripartite regulatory network, achieving molecular-level metabolic modulation through enhanced AMPKα-Thr172 phosphorylation, reduced SREBP-1c nuclear translocation, and downregulated FAS and ACC expression. Notably, FX simultaneously activates both AMPK and the Nrf2 signaling pathway, orchestrating coordinated redox homeostasis remodeling and inflammatory microenvironment regulation via suppression of the TLR4/MyD88/NF-κB cascade, ultimately reducing TNF-α/IL-6 secretion (Mumu et al., 2022; Ye et al., 2022). Of particular significance, Dictyophora indusiata (D. indusiata) exhibits distinctive “metabolic reprogramming” capabilities through: 1) allosteric activation of the AMPKγ subunit to enhance CPT1α promoter activity; 2) epigenetic modulation of CD36 gene promoter histone deacetylation (H3K9ac); and 3) activation of the AMPK/PGC-1α/UCP2 axis to improve mitochondrial respiratory efficiency, thereby establishing a comprehensive regulatory framework spanning gene expression to organelle function (Hu et al., 2023). These groundbreaking discoveries not only transcend the limitations of conventional single-target therapies but also, through innovative mechanisms including establishing “metabolic checkpoint” networks, mediating inter-organelle communication, and regulating epigenetic modifications, provide transformative perspectives for developing precision NAFLD therapeutics based on polysaccharide metabolites and pioneer new directions for AMPK-targeted drug discovery.
5.10 Quinones
Quinone metabolites, as emerging stars in the field of NAFLD therapy, are reshaping the treatment paradigms for metabolic diseases. Recent studies have revealed that these naturally occurring molecules—with their unique redox properties—exhibit multidimensional therapeutic advantages over conventional drugs by delicately modulating the “metabolism-inflammation” crosstalk within the AMPK signaling network. Rhinacanthin C (RC), a representative quinone metabolite characterized by its distinctive conjugated double-bond structure, has achieved three groundbreaking advancements in the treatment of NAFLD: (1) Dual Regulatory Switch: RC establishes a “energy sensing-epigenetic regulation” dual switch mechanism through allosteric activation of the AMPKα subunit (Thr172 phosphorylation ↑ 2.8-fold) and enhancement of SIRT1 activity (↑ 1.9-fold); (2) Simultaneous Metabolic and Insulin Sensitivity Improvement: It innovatively modulates both insulin resistance (HOMA-IR ↓ 42%) and lipid metabolism (TG ↓ 55%) via the miR-34a/SIRT1 feedback loop; (3) Integrated Anti-inflammatory and Antioxidant Effects: Most notably, the unique electron transfer capability of RC’s quinone structure enables it to concurrently regulate the NF-κB inflammatory pathway (p-p65 ↓ 60%) and oxidative stress responses, achieving a “trinity-like” intervention targeting the core pathological metabolites of NAFLD. This multitarget pharmacological profile not only overcomes the limitations of current therapeutic agents but also opens up a novel strategy for treating metabolic disorders based on the electron transport properties of quinone metabolites (Gong et al., 2023).
5.11 Other classes
Beyond these findings, other natural bioactive metabolites demonstrate remarkable therapeutic potential for NAFLD through modulation of the AMPK signaling pathway. Research reveals that CY-10 extract from Silphium perfoliatum, containing 50% chlorogenic acids, reduces lipogenesis and promotes lipid oxidation via the AMPK/FXR/SREBP-1C/PPAR-γ pathway (Zhang G. et al., 2025; Xu et al., 2024). Royal jelly (RJ) downregulates SREBP1c through AMPK/PPARα signaling while elevating hepatic GSH and SOD levels and reducing MDA and inflammatory factors (Felemban et al., 2023). The combination of luteolin and lycopene ameliorates steatosis through the NAMPT/NAD+/SIRT1/AMPK axis while suppressing the NF-κB inflammatory pathway (Zhu et al., 2020). Notably, the mixture of Peanut Skin Extract, Geniposide and Isoquercitrin (MPGI) significantly improves hepatic steatosis through coordinated multi-pathway actions (TLR4/NF-κB, AMPK/ACC/CPT1) (Yi et al., 2023). Furthermore, mustard extract (Sheu et al., 2023), Salvia plebeia R. Br. Water extract (Bae et al., 2022), Meconopsis integrifolia extract (Guo et al., 2016; Lu et al., 2024), and Coix lacryma-jobi seed oil (Gu et al., 2021) all ameliorate lipid metabolic disorders by regulating AMPK and its downstream targets (SREBP1, ACC, PPARα). Recent studies identify additional metabolites - including Lygodium microphyllum (Anggreini et al., 2024), sea grape extract (Sangpairoj et al., 2024), erianin (He et al., 2022; Li H. et al., 2024), Sophora moorcroftiana seed ethanol extract (Wang T. et al., 2024; Gao, 2024), fraxin (Cheng, 2024), and corilagin (Liao et al., 2022; Wang J. et al., 2023) - that not only activate AMPK but also synergistically improve NAFLD through gut microbiota modulation, enhanced autophagy, and antioxidant effects. Particularly noteworthy, Cassia seed aqueous extract inhibits FASN expression via the AMPK/TFEB-mediated autophagy pathway (Ding, 2023), while acetylated S. rugoso-annulata polysaccharides exert anti-NAFLD effects through a triple regulatory network involving Nrf2/HO-1, JNK1/AP-1 and AMPK (Li, 2023). Eucommia ulmoides leaf extracts have also been shown to enhance lipid oxidation via the AMPK/PPARα/CPT-1A pathway (Cai et al., 2022). These collective findings demonstrate that natural bioactive metabolites targeting the AMPK pathway employ a multidimensional mechanism of “lipid metabolism regulation-insulin resistance improvement-inflammatory suppression-oxidative stress reduction”, providing abundant candidate substances for NAFLD treatment.
6 Limitations of preclinical evidence and appraisal of translational gaps
While current clinical management of NAFLD primarily relies on lifestyle modifications and metabolic regulation interventions—including insulin sensitizers, antioxidants, and lipid-lowering agents—these approaches can delay disease progression but rarely reverse hepatic steatosis and fibrosis. Recent studies have highlighted the unique advantages of TCM and its bioactive metabolites in modulating AMPK signaling pathways, improving lipid metabolism, and suppressing inflammation and oxidative stress, offering novel therapeutic strategies for NAFLD.
Multiple experimental and clinical trials have preliminarily confirmed TCM’s efficacy and safety. For instance, metabolite formulas like Zexie-Baizhu Decoction and Xiaozhi formula synergistically activate key signaling pathways, including AMPK/SREBP-1c and AMPK/mTOR, effectively reducing hepatic fat accumulation and insulin resistance (Cao et al., 2022; You et al., 2024; Luo et al., 2025; Liu W. et al., 2022). The modified silymarin formulation demonstrates enhanced bioavailability and shows promising anti-NAFLD activity in preclinical models (Cai, 2024). Clinical trials also reveal that TCM interventions such as Shugan-Hewei Decoction and Hedan Capsules improve liver function, lipid profiles, and liver stiffness without significant adverse effects (Lin, 2023; Lin, 2025). These findings suggest that TCM monotherapy or combination with existing Western medications could serve as effective complementary or even alternative strategies for comprehensive NAFLD management.
Notably, the current body of evidence supporting TCM-based AMPK modulation in NAFLD is largely constrained by limitations in preclinical research, which hinder robust translational inference. First, in vitro studies predominantly use immortalized cell lines (e.g., HepG2, L02) or primary hepatocytes under simplified lipid overload conditions, failing to recapitulate the complex in vivo microenvironment of NAFLD—including crosstalk between hepatocytes, hepatic stellate cells, and immune cells, or systemic metabolic dysregulation. This oversimplification may overestimate the direct AMPK-mediated effects of natural products, as cell-autonomous responses often differ from tissue-level regulation in intact organisms.
Second, animal models of NAFLD, though valuable, have critical drawbacks. High-fat diet-induced murine models typically develop only mild steatosis without the progressive fibrosis or metabolic comorbidities (e.g., type 2 diabetes) that characterize human NAFLD. Genetically engineered models (e.g., ob/ob, db/db mice) better mimic metabolic dysfunction but exhibit phenotypic divergence from human disease, such as accelerated hepatocellular injury unrelated to natural disease progression. Consequently, the AMPK-dependent mechanisms observed in these models—such as altered SREBP-1c-mediated lipogenesis or mTOR-regulated autophagy—may not fully translate to human pathophysiology.
Third, preclinical studies often lack standardized methodologies, limiting reproducibility. Variability in natural product extraction protocols (e.g., solvent type, purification steps) leads to inconsistent bioactive metabolite profiles, making it difficult to attribute observed effects to specific AMPK modulators. Additionally, most studies measure AMPK activity via single time-point assessments of p-AMPK Thr172, without quantifying downstream pathway dynamics (e.g., ACC phosphorylation, ULK1 activation) or tissue-specific AMPK isoform expression—critical for understanding context-dependent regulation in NAFLD.
Finally, translational gaps persist due to limited clinical validation. While small-scale trials suggest benefits of TCM interventions, high-quality evidence from large, multi-center randomized controlled trials (RCTs) is scarce. Existing clinical studies often lack rigorous AMPK activity monitoring (e.g., longitudinal tracking of p-AMPK in liver biopsies or surrogate biomarkers) and long-term safety data, particularly regarding drug-drug interactions in patients on concurrent metabolic therapies.
To address these limitations, future research should prioritize: (1) developing more physiologically relevant preclinical models (e.g., humanized liver chimeras, diet-induced murine models with metabolic comorbidities) to better recapitulate human NAFLD pathophysiology; (2) standardizing natural product extraction and characterization to ensure consistent AMPK-modulating activity (3) integrating multi-omics approaches (e.g., phosphoproteomics, single-cell RNA sequencing); to dissect tissue-specific AMPK signaling networks; and (4) conducting well-designed RCTs with validated AMPK activity markers (e.g., p-AMPK Thr172 in peripheral blood mononuclear cells or liver tissue) to establish causal links between TCM-mediated AMPK activation and clinical outcomes. By addressing these critical gaps, the translational potential of TCM-derived AMPK modulators in NAFLD management can be more rigorously evaluated.
7 Summary and prospect
NAFLD has emerged as the leading cause of chronic liver disease worldwide. Its global prevalence continues to rise, posing a significant threat to public health. The AMPK signaling pathway plays a core role in the regulation of energy metabolism, lipid metabolism, inflammation, and autophagy and has become an important target for the prevention and treatment of NAFLD. In recent years, natural products have shown unique advantages in improving NAFLD by activating the AMPK signaling pathway. Studies have shown that the decline in AMPK activity leads to an increase in lipid synthesis, obstruction of fatty acid oxidation, enhanced oxidative stress, and activation of inflammation, while natural products can restore energy metabolic homeostasis through the AMPK pathway. Active metabolites such as terpenoids, phenols, flavonoids, and lignans can promote the phosphorylation of AMPK, increase the oxidation level of fatty acids, reduce lipid accumulation, and inhibit the activation of inflammatosomes. In addition, AMPK can also regulate pathways such as mTOR, autophagy, and Nrf2, alleviating oxidative damage and metabolic imbalance related to NAFLD.
Notably, although plant metabolites such as berberine, emodin and curcumin have been shown in vitro to improve NAFLD symptoms by regulating hepatic lipid metabolism and inhibiting hepatocellular inflammation, they are categorized as pan-assay interference compounds (PAINS), which may generate false-positive results in vitro through non-specific mechanisms (Magalhães et al., 2021). Their specific effects and mechanisms need to be further validated in more physiologically relevant models or in vivo studies to exclude assay interference. Moreover, some studies did not provide cell viability data to demonstrate the minimum effective concentration and confirm that these compounds are non-toxic at such concentrations. Therefore, these findings require further validation in primary hepatocytes or in vivo NAFLD models.
Although significant progress has been made in the research on the regulation of the AMPK pathway by natural products to intervene in NAFLD, the following key problems still need to be solved urgently. Most of the existing studies have focused on the regulation of core molecules of the AMPK pathway (such as ACC, mTOR, and SEBP-1C), but its interaction with other metabolic pathways (such as PI3K/Akt, FGF21, and the gut microbiota-liver axis) has not been fully clarified, which limits the comprehensive understanding of the complex regulatory network in NAFLD. Secondly, the specific functional differences of AMPK isoforms (α1/α2, β1/β2, γ1/γ2/γ3) in the pathological process of NAFLD remain unclear, and isoform-selective regulation may become a key breakthrough for precise treatment. Thirdly, long-term application of natural products may affect energy metabolism in extrahepatic tissues (such as muscle and adipose tissue) through the AMPK pathway. Currently, there is a lack of systematic toxicity evaluation data regarding their systemic effects, and it is urgent to establish an AMPK pathway-dependent toxicity early warning model to ensure the safety of clinical application by assessing the potential effects of natural product metabolites on extrahepatic organs.
As a core target for NAFLD treatment, the AMPK signaling pathway also provides an important entry point for TCM intervention. Future research needs to achieve breakthroughs in the following aspects: deepening the mechanistic analysis of the crosstalk network between the AMPK pathway and multiple other pathways; clarifying the synergistic regulatory rules of TCM metabolite prescriptions characterized by “multi-metabolites and multi-targets”; and promoting the integration of interdisciplinary technologies (such as multi-omics and targeted delivery technologies) to accelerate research translation. Through the aforementioned efforts, a more solid scientific basis can be provided for the development of innovative drugs targeting AMPK, ultimately achieving precise prevention and treatment of NAFLD.
Author contributions
CZ: Writing – original draft, Writing – review and editing. JS: Supervision, Writing – review and editing. LS: Conceptualization, Supervision, Writing – review and editing.
Funding
The authors declare that no financial support was received for the research and/or publication of this article.
Acknowledgements
Figure l and Figure 2 were created with FigDraw.
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 authors declare that no Generative AI was used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
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
Anggreini, P., Kuncoro, H., Sumiwi, S. A., and Levita, J. (2024). Lygodium microphyllum Inhibits de novo Lipogenesis Activity in the Hepatocytes of High-Fat High-Fructose-Induced Rats by Increasing the Levels of SIRT1 and AMPK. J. Exp. Pharmacol. 16, 351–364. doi:10.2147/JEP.S473763
Atteia, H. H., AlFaris, N. A., Alshammari, G. M., Alamri, E., Ahmed, S. F., Albalwi, R., et al. (2023). The hepatic antisteatosis effect of xanthohumol in high-fat diet-fed rats entails activation of AMPK as a possible protective mechanism. Foods 12 (23), 4214. doi:10.3390/foods12234214
Bae, S., Lee, Y. H., Lee, J., Park, J., Jun, W., and Salvia plebeia, R.Br (2022). Salvia plebeia R. Br. Water extract ameliorates hepatic steatosis in a non-alcoholic fatty liver disease model by regulating the AMPK pathway. Nutrients 14 (24), 5379. doi:10.3390/nu14245379
Bai, J., Zhang, Y., Tang, C., Hou, Y., Ai, X., Chen, X., et al. (2021). Gallic acid: pharmacological activities and molecular mechanisms involved in inflammation-related diseases. Biomed. Pharmacother. 133, 110985. doi:10.1016/j.biopha.2020.110985
Bakun, P., Mlynarczyk, D. T., Koczorowski, T., Cerbin-Koczorowska, M., Piwowarczyk, L., Kolasiński, E., et al. (2023). Tea-break with epigallocatechin gallate derivatives - powerful polyphenols of great potential for medicine. Eur. J. Med. Chem. 261, 115820. doi:10.1016/j.ejmech.2023.115820
Bi, Z., Zhang, W., and Yan, X. (2022). Anti-inflammatory and immunoregulatory effects of icariin and icaritin. Biomed. Pharmacother. 151, 113180. doi:10.1016/j.biopha.2022.113180
Cai, J. (2024). Preparation of silybin liposomes and its effect on the improvement of T2DM-NAFLD[D]. Hunan Univ. Chin. Med. doi:10.27138/d.cnki.ghuzc.2024.000006
Cai, D., Zhou, C., Zhang, Z., Zhao, Y., Bian, Y., Xue, M., et al. (2022). Eucommia folium extracts alleviate nonalcoholic fatty liver disease in vivo and in vitro based on the network pharmacology study. J. Nanjing Univ. Tradit. Chin. Med. 38 (08), 703–716. doi:10.14148/j.issn.1672-0482.2022.0703
Cao, Y., Shi, J., Song, L., Xu, J., Lu, H., Sun, J., et al. (2022). Multi-omics integration analysis identifies lipid disorder of a non-alcoholic fatty liver disease (NAFLD) mouse model improved by Zexie-Baizhu decoction. Front. Pharmacol. 13, 858795. doi:10.3389/fphar.2022.858795
Cao, P., Wang, Y., Zhang, C., Sullivan, M. A., Chen, W., Jing, X., et al. (2023). Quercetin ameliorates nonalcoholic fatty liver disease (NAFLD) via the promotion of AMPK-Mediated hepatic mitophagy. J. Nutr. Biochem. 120, 109414. doi:10.1016/j.jnutbio.2023.109414
Chang, T. C., Chiou, W. C., Lai, W. H., Huang, H. C., Huang, Y. L., Liu, H. K., et al. (2021). Ugonin J improves metabolic disorder and ameliorates nonalcoholic fatty liver disease by regulating the AMPK/AKT signaling pathway. Pharmacol. Res. 163, 105298. doi:10.1016/j.phrs.2020.105298
Chen, W., Zhang, X., Xu, M., Jiang, L., Zhou, M., Liu, W., et al. (2021). Betaine prevented high-fat diet-induced NAFLD by regulating the FGF10/AMPK signaling pathway in ApoE-/- mice. Eur. J. Nutr. 60 (3), 1655–1668. doi:10.1007/s00394-020-02362-6
Chen, H., Nie, T., Zhang, P., Ma, J., and Shan, A. (2022). Hesperidin attenuates hepatic lipid accumulation in mice fed high-fat diet and oleic acid induced HepG2 via AMPK activation. Life Sci. 296, 120428. doi:10.1016/j.lfs.2022.120428
Cheng, J. (2024). Mechanism of action of qinpiin on non-alcoholic fatty liverdisease in high-fat diet-fed mice via the AMPK/Nrf2 pathway and gut microbiota. [Dissertation/Master’s thesis] Jilin, China: Jilin University. doi:10.27162/d.cnki.gjlin.2024.006696
Cheng, L., Deepak, RNVK, Wang, G., Meng, Z., Tao, L., Xie, M., et al. (2023). Hepatic mitochondrial NAD + transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis. Hepatology 78 (6), 1828–1842. doi:10.1097/HEP.0000000000000314
Dai, T. Y., Lan, J. J., Gao, R. L., Zhao, Y. N., Yu, X. L., Liang, S. X., et al. (2022). Panaxdiol saponins component promotes hematopoiesis by regulating GATA transcription factors of intracellular signaling pathway in mouse bone marrow. Ann. Transl. Med. 10 (2), 38. doi:10.21037/atm-21-4800
Ding, M. (2023). Study on the effects and mechanisms of cassia seed on ameliorating non-alcoholic fatty liver disease via the AMPK-autophagy pathway. [Dissertation/Master’s thesis]. Beijing, China: Beijing University of Chinese Medicine. doi:10.26973/d.cnki.gbjzu.2023.000964
Ding, Y., Chen, Y., Hu, K., Yang, Q., Li, Y., and Huang, M. (2023). Sweroside alleviates hepatic steatosis in part by activating AMPK/mTOR-mediated autophagy in mice. J. Cell Biochem. 124 (7), 1012–1022. doi:10.1002/jcb.30428
Dou, C., Zhu, H., Xie, X., Huang, C., and Cao, C. (2024). Integrated pharmaco-bioinformatics approaches and experimental verification to explore the effect of britanin on nonalcoholic fatty liver disease. ACS Omega 9 (7), 8274–8286. doi:10.1021/acsomega.3c08968
Du, S., Chen, X., Ren, R., Li, L., Zhang, B., Wang, Q., et al. (2024). Integration of network pharmacology, lipidomics, and transcriptomics analysis to reveal the mechanisms underlying the amelioration of AKT-Induced nonalcoholic fatty liver disease by total flavonoids in Vine tea. Food Funct. 15 (9), 5158–5174. doi:10.1039/d4fo00586d
Eslam, M., Sanyal, A. J., George, J., and International, C. P. (2020). MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158 (7), 1999–2014.e1. doi:10.1053/j.gastro.2019.11.312
Fan, W., Pan, M., Zheng, C., Shen, H., Pi, D., Song, Q., et al. (2024). Leonurine inhibits hepatic lipid synthesis to ameliorate NAFLD via the ADRA1a/AMPK/SCD1 axis. Int. J. Mol. Sci. 25 (19), 10855. doi:10.3390/ijms251910855
Fang, Y., Pan, J., Wang, P., Wang, R., and Liang, S. (2025). A comprehensive review of schisandrin B's preclinical antitumor activity and mechanistic insights from network pharmacology. Front. Pharmacol. 16, 1528533. doi:10.3389/fphar.2025.1528533
Farooqi, A. A., Wen, R., Attar, R., Taverna, S., Butt, G., and Xu, B. (2022). Regulation of cell-signaling pathways by berbamine in different cancers. Int. J. Mol. Sci. 23 (5), 2758. doi:10.3390/ijms23052758
Felemban, A. H., Alshammari, G. M., Yagoub, A. E. A., Al-Harbi, L. N., Alhussain, M. H., and Yahya, M. A. (2023). Activation of AMPK entails the protective effect of royal jelly against high-fat-diet-induced hyperglycemia, hyperlipidemia, and non-alcoholic fatty liver disease in rats. Nutrients 15 (6), 1471. doi:10.3390/nu15061471
Fu, L., Wu, Z., Chu, Y., Chen, W., Gao, L., Mu, S., et al. (2022). Explore the mechanism of Astragalus mongholicus bunge against nonalcoholic fatty liver disease based on network pharmacology and experimental verification. Gastroenterol. Res. Pract. 2022, 4745042. doi:10.1155/2022/4745042
Gao, L. (2024). Effect and mechanism of sophora moocroftiana (benth.)Benth.Ex baker seeds on NAFLD lipid metabolis. Qingdao Univ. Sci. Technol. doi:10.27264/d.cnki.gqdhc.2024.000113
Gao, S., and Feng, Q. (2022). The beneficial effects of geniposide on glucose and lipid metabolism: a review. Drug Des. Devel Ther. 16, 3365–3383. doi:10.2147/DDDT.S378976
Gao, J., Zhang, Y., Liu, X., Wu, X., Huang, L., and Gao, W. (2021). Triptolide: pharmacological spectrum, biosynthesis, chemical synthesis and derivatives. Theranostics 11 (15), 7199–7221. doi:10.7150/thno.57745
Gao, C., Zhang, H., Nie, L., He, K., Li, P., Wang, X., et al. (2023). Chrysin prevents inflammation-coinciding liver steatosis via AMPK signalling. J. Pharm. Pharmacol. 75 (8), 1086–1099. doi:10.1093/jpp/rgad041
Gnoni, A., Di Chiara Stanca, B., Giannotti, L., Gnoni, G. V., Siculella, L., and Damiano, F. (2022). Quercetin Reduces Lipid Accumulation in a Cell Model of NAFLD by Inhibiting de novo Fatty Acid Synthesis through the Acetyl-CoA Carboxylase 1/AMPK/PP2A Axis. Int. J. Mol. Sci. 23 (3), 1044. doi:10.3390/ijms23031044
Gong, Z., Han, S., Li, C., Meng, T., Huo, Y., Liu, X., et al. (2023). Rhinacanthin C ameliorates insulin resistance and lipid accumulation in NAFLD mice via the AMPK/SIRT1 and SREBP-1c/FAS/ACC signaling pathways. Evid. Based Complement. Altern. Med. 2023, 6603522. doi:10.1155/2023/6603522
Gu, L., Zhang, Y., Zhang, S., Zhao, H., Wang, Y., Kan, D., et al. (2021). Coix lacryma-jobi seed oil reduces fat accumulation in nonalcoholic fatty liver disease by inhibiting the activation of the p-AMPK/SePP1/apoER2 pathway. J. Oleo Sci. 70 (5), 685–696. doi:10.5650/jos.ess20255
Guo, Q., Bai, R., Zhao, B., Feng, X., Zhao, Y., Tu, P., et al. (2016). An ethnopharmacological, phytochemical and pharmacological review of the genus meconopsis. Am. J. Chin. Med. 44 (3), 439–462. doi:10.1142/S0192415X16500257
Guo, Y., Zhao, L., Chang, B., Yu, J., Bao, J., Yao, Q., et al. (2022). The traditional uses, phytochemistry, pharmacokinetics, pharmacology, toxicity, and applications of Corydalis saxicola bunting: a review. Front. Pharmacol. 13, 822792. doi:10.3389/fphar.2022.822792
Guo, Y., Sun, Q., Wang, S., Zhang, M., Lei, Y., Wu, J., et al. (2024). Corydalis saxicola Bunting total alkaloids improve NAFLD by suppressing de novo lipogenesis through the AMPK-SREBP1 axis. J. Ethnopharmacol. 319 (Pt 1), 117162. doi:10.1016/j.jep.2023.117162
Harrison, S. A., Bedossa, P., Guy, C. D., Schattenberg, J. M., Loomba, R., Taub, R., et al. (2024). A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N. Engl. J. Med. 390 (6), 497–509. doi:10.1056/NEJMoa2309000
He, J., Long, X., Nie, C., Zhao, X., Wang, W., and Zhu, Q. (2022). Bioinformatics and expression analysis of BBS gene family in Dendrobium officinale. Genom Appl. Biol. 41 (06), 1329–1338. doi:10.13417/j.gab.041.001329
He, C., Wang, H., Zhou, B., Kong, J., and Wang, X. (2024). Clinical efficacy of qushi huayu granules in treating non-alcoholic fatty liver disease (NAFLD) with dampness-heat accumulation. Chin J Exp Tradit Med Formulae 30 (18), 139–145. doi:10.13422/j.cnki.syfjx.20242195
Hu, T., Lu, J., and Luo, P. (2023). “Effect of Dictyophora indusiata polysaccharides on the hepatic AMPK/CPT1 pathway in high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mice[C],” in Proceedings of the 10th National Congress of the Chinese Society of Toxicology. Editor W. Zhang. Guiyang, China: Guizhou Medical University Press 2023-04-08, 214–215. doi:10.26914/c.cnkihy.2023.012063
Huang, R., Guo, F., Li, Y., Liang, Y., Li, G., Fu, P., et al. (2021). Activation of AMPK by triptolide alleviates nonalcoholic fatty liver disease by improving hepatic lipid metabolism, inflammation and fibrosis. Phytomedicine 92, 153739. doi:10.1016/j.phymed.2021.153739
Jie, F., Yang, X., Yang, B., Liu, Y., Wu, L., and Lu, B. (2022). Stigmasterol attenuates inflammatory response of microglia via NF-κB and NLRP3 signaling by AMPK activation. Biomed. Pharmacother. 153, 113317. doi:10.1016/j.biopha.2022.113317
Kim, H., Seo, K. H., and Yokoyama, W. (2020). Chemistry of pterostilbene and its metabolic effects. J. Agric. Food Chem. 68 (46), 12836–12841. doi:10.1021/acs.jafc.0c00070
Kim, S. H., Yun, C., Kwon, D., Lee, Y. H., Kwak, J. H., and Jung, Y. S. (2023). Effect of isoquercitrin on free fatty acid-induced lipid accumulation in HepG2 cells. Molecules 28 (3), 1476. doi:10.3390/molecules28031476
Li, X. (2023). Alleviative effect of acetylated polysaccharides from strophariarugoso-Annulata on non-alcoholic fatty liver disease in mice. Shandong Agric. Univ. doi:10.27277/d.cnki.gsdnu.2023.000213
Li, S. L., Cao, R., Hu, X. F., Xiong, P., Zhao, G. Y., Xie, Y. N., et al. (2021). Daidzein ameliorated concanavalin A-induced liver injury through the Akt/GSK-3β/Nrf2 pathway in mice. Ann. Transl. Med. 9 (15), 1228. doi:10.21037/atm-21-378
Li, P., Zhang, R., Wang, M., Chen, Y., Chen, Z., Ke, X., et al. (2022a). Baicalein Prevents Fructose-Induced Hepatic Steatosis in Rats: in the Regulation of Fatty Acid de novo Synthesis, Fatty Acid Elongation and Fatty Acid Oxidation. Front. Pharmacol. 13, 917329. doi:10.3389/fphar.2022.917329
Li, Q., Tan, J. X., He, Y., Bai, F., Li, S. W., Hou, Y. W., et al. (2022b). Atractylenolide III ameliorates non-alcoholic fatty liver disease by activating hepatic adiponectin receptor 1-Mediated AMPK pathway. Int. J. Biol. Sci. 18 (4), 1594–1611. doi:10.7150/ijbs.68873
Li, H., Wang, C., Wang, Q., Liu, X., Zhang, J., Zhang, H., et al. (2023). Oxymatrine alleviates high-fat-high-fructose-induced fatty liver in rats: understanding the molecular mechanism through an untargeted metabonomics study. Diabetes Metab. Syndr. Obes. 16, 4013–4024. doi:10.2147/DMSO.S428864
Li, B., Xiao, Q., Zhao, H., Zhang, J., Yang, C., Zou, Y., et al. (2024a). Schisanhenol ameliorates non-alcoholic fatty liver disease via inhibiting miR-802 activation of AMPK-Mediated modulation of hepatic lipid metabolism. Acta Pharm. Sin. B 14 (9), 3949–3963. doi:10.1016/j.apsb.2024.05.014
Li, H., Zhou, Z., Hou, Y., Li, Z., Wu, W., and Xu, B. (2024b). Investigation of the effects and related mechanisms of erianin on non-alcoholic fatty liver disease in Mice[J/OL]. J. Chin. Med. Mater (11), 2876–2879. [2025-04-30]. doi:10.13863/j.issn1001-4454.2024.11.033
Lian, Y. (2022). Protective effect of bergenin on nonalcoholic fattyliver disease and its mechanism. GuiLin Med. Univ. doi:10.27806/d.cnki.gglyx.2022.000171
Liang, L., Ye, S., Jiang, R., Zhou, X., Zhou, J., and Meng, S. (2022). Liensinine alleviates high fat diet (HFD)-Induced non-alcoholic fatty liver disease (NAFLD) through suppressing oxidative stress and inflammation via regulating TAK1/AMPK signaling. Int. Immunopharmacol. 104, 108306. doi:10.1016/j.intimp.2021.108306
Liao, M., Zhang, R., Wang, Y., Mao, Z., Wu, J., Guo, H., et al. (2022). Corilagin prevents non-alcoholic fatty liver disease via improving lipid metabolism and glucose homeostasis in high fat diet-fed mice. Front. Nutr. 9, 983450. doi:10.3389/fnut.2022.983450
Liao, T., Mei, W., Zhang, L., Ding, L., Yang, N., Wang, P., et al. (2023). L-carnitine alleviates synovitis in knee osteoarthritis by regulating lipid accumulation and mitochondrial function through the AMPK-ACC-CPT1 signaling pathway. J. Orthop. Surg. Res. 18 (1), 386. doi:10.1186/s13018-023-03872-9
Lin, Z. (2023). Explore the clinical observation and mechanism study of shugan hewei decoction inhibiting oxidative stress about thetreatment of non-alcoholic fatty liver disease based on AMPK/SIRT1/PGC-1α signaling pathway. Guangxi Univ. Chin. Med. doi:10.27879/d.cnki.ggxzy.2023.000601
Lin, J. (2025). Molecular mechanisms and clinical efficacy of HeDan capsule in the treatment of nonalcoholic fatty liver disease based on a multi-omics integration strategy [Dissertation/Master’s thesis]. China, Fuzhou: Fujian University of Traditional Chinese Medicine. doi:10.27021/d.cnki.gfjzc.2025.000034
Lin, W., Jin, Y., Hu, X., Huang, E., and Zhu, Q. (2021). AMPK/PGC-1α/GLUT4-Mediated effect of icariin on hyperlipidemia-induced non-alcoholic fatty liver disease and lipid metabolism disorder in mice. Biochem. (Mosc). 86 (11), 1407–1417. doi:10.1134/S0006297921110055
Liu, J., Zhang, T., Zhu, J., Ruan, S., Li, R., Guo, B., et al. (2021a). Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3-AMPK-mediated lipophagy. Chin. Med. 16 (1), 115. doi:10.1186/s13020-021-00528-w
Liu, M. Y., Liu, F., Gao, Y. L., Yin, J. N., Yan, W. Q., Liu, J. G., et al. (2021b). Pharmacological activities of ginsenoside Rg5 (review). Exp. Ther. Med. 22 (2), 840. (Review). doi:10.3892/etm.2021.10272
Liu, X., Huang, Y., Liang, X., Wu, Q., Wang, N., Zhou, L. J., et al. (2022a). Atractylenolide III from Atractylodes macrocephala koidz promotes the activation of brown and white adipose tissue through SIRT1/PGC-1α signaling pathway. Phytomedicine 104, 154289. doi:10.1016/j.phymed.2022.154289
Liu, W., Shang, J., Deng, Y., Han, X., Chen, Y., Wang, S., et al. (2022b). Network pharmacology analysis on mechanism of jian Pi qing gan yin decoction ameliorating high fat diet-induced non-alcoholic fatty liver disease and validated in vivo. J. Ethnopharmacol. 295, 115382. doi:10.1016/j.jep.2022.115382
Liu, P., Anandhan, A., Chen, J., Shakya, A., Dodson, M., Ooi, A., et al. (2023). Decreased autophagosome biogenesis, reduced NRF2, and enhanced ferroptotic cell death are underlying molecular mechanisms of non-alcoholic fatty liver disease. Redox Biol. 59, 102570. doi:10.1016/j.redox.2022.102570
Liu, S., Sun, C., Tang, H., Peng, C., and Peng, F. (2024). Leonurine: a comprehensive review of pharmacokinetics, pharmacodynamics, and toxicology. Front. Pharmacol. 15, 1428406. doi:10.3389/fphar.2024.1428406
Lonardo, A., Bril, F., Caldwell, S. H., Eslam, M., Fan, J. G., Gish, R. G., et al. (2024). Researchers call for more flexible editorial conduct rather than abruptly adopting only the new MASLD nomenclature. J. Hepatol. 80 (5), e192–e194. doi:10.1016/j.jhep.2024.01.012
Lu, Y., Guan, T., Xu, S., Chen, Y. E., Shen, Q., Zhu, S., et al. (2022). Asperuloside inhibited epithelial-mesenchymal transition in colitis associated cancer via activation of vitamin D receptor. Phytomedicine 101, 154070. doi:10.1016/j.phymed.2022.154070
Lu, Y., Zhang, C., Song, Y., Chen, L., Chen, X., Zheng, G., et al. (2023). Gallic acid impairs fructose-driven de novo lipogenesis and ameliorates hepatic steatosis via AMPK-dependent suppression of SREBP-1/ACC/FASN cascade. Eur. J. Pharmacol. 940, 175457. doi:10.1016/j.ejphar.2022.175457
Lu, Q., La, M., Wang, Z., Huang, J., Zhu, J., and Zhang, D. (2024). Investigation of active components of Meconopsis integrifolia (maxim.) franch in mitigating non-alcoholic fatty liver disease. Int. J. Mol. Sci. 26 (1), 50. doi:10.3390/ijms26010050
Luo, X., Fang, Y., Wang, W., Tong, M., Qin, B., Cao, J., et al. (2025). Yinchen lipid-lowering tea attenuates lipid deposition in a fatty liver model by regulating mitochondrial dysfunction through activation of AdipoR1/AMPK/SIRT1 signaling. 3 Biotech. 15 (2), 39. doi:10.1007/s13205-024-04204-2
Lv, T., Fan, X., He, C., Zhu, S., Xiong, X., Yan, W., et al. (2024). SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression. Redox Biol. 72, 103159. doi:10.1016/j.redox.2024.103159
Ma, S., Yang, B., Shi, Y., Du, Y., Lv, Y., Liu, J., et al. (2022). Adlay (Coix lacryma-jobi L.) polyphenol improves hepatic glucose and lipid homeostasis through regulating intestinal flora via AMPK pathway. Mol. Nutr. Food Res. 66 (23), e2200447. doi:10.1002/mnfr.202200447
Ma, Q. G., He, N. X., Huang, H. L., Fu, X. M., Zhang, Z. L., Shu, J. C., et al. (2023a). Hippophae rhamnoides L.: a comprehensive review on the botany, traditional uses, phytonutrients, health benefits, quality markers, and applications. J. Agric. Food Chem. 71 (12), 4769–4788. doi:10.1021/acs.jafc.2c06916
Ma, X., Guo, Z., Zhao, W., and Chen, L. (2023b). Sweroside plays a role in mitigating high glucose-induced damage in human renal tubular epithelial HK-2 cells by regulating the SIRT1/NF-κB signaling pathway. Korean J. Physiol. Pharmacol. 27 (6), 533–540. doi:10.4196/kjpp.2023.27.6.533
Magalhães, P. R., Reis, PBPS, Vila-Viçosa, D., Machuqueiro, M., and Victor, B. L. (2021). Identification of pan-assay INterference compoundS (PAINS) using an MD-Based protocol. Methods Mol. Biol. 2315, 263–271. doi:10.1007/978-1-0716-1468-6_15
Maharajan, N., and Cho, G. W. (2021). Camphorquinone promotes the antisenescence effect via activating AMPK/SIRT1 in stem cells and D-Galactose-Induced aging mice. Antioxidants (Basel). 10 (12), 1916. doi:10.3390/antiox10121916
Maharajan, N., Kim, K. H., Vijayakumar, K. A., and Cho, G. W. (2025). Unlocking therapeutic potential: camphorquinone's role in alleviating non-alcoholic fatty liver disease via SIRT1/LKB1/AMPK pathway activation. Tissue Eng. Regen. Med. 22 (1), 129–144. doi:10.1007/s13770-024-00684-8
Marcondes-de-Castro, I. A., Reis-Barbosa, P. H., Marinho, T. S., Aguila, M. B., and Mandarim-de-Lacerda, C. A. (2023). AMPK/mTOR pathway significance in healthy liver and non-alcoholic fatty liver disease and its progression. J. Gastroenterol. Hepatol. 38 (11), 1868–1876. doi:10.1111/jgh.16272
Mi, A., Hu, Q., Liu, Y., Zhao, Y., Shen, F., Lan, J., et al. (2024). Hepatoprotective efficacy and interventional mechanism of the panaxadiol saponin component in high-fat diet-induced NAFLD mice. Food Funct. 15 (2), 794–808. doi:10.1039/d3fo03572g
Mishra, A., Mishra, P. S., Bandopadhyay, R., Khurana, N., Angelopoulou, E., Paudel, Y. N., et al. (2021). Neuroprotective potential of chrysin: mechanistic insights and therapeutic potential for neurological disorders. Molecules 26 (21), 6456. doi:10.3390/molecules26216456
Mohammed, H. M. (2022). Zingerone ameliorates non-alcoholic fatty liver disease in rats by activating AMPK. J. Food Biochem. 46 (7), e14149. doi:10.1111/jfbc.14149
Mumu, M., Das, A., Emran, T. B., Mitra, S., Islam, F., Roy, A., et al. (2022). Fucoxanthin: a promising phytochemical on diverse pharmacological targets. Front. Pharmacol. 13, 929442. doi:10.3389/fphar.2022.929442
Muraleedharan, R., and Dasgupta, B. (2022). AMPK in the brain: its roles in glucose and neural metabolism. FEBS J. 289 (8), 2247–2262. doi:10.1111/febs.16151
Nassir, F. (2022). NAFLD: mechanisms, treatments, and biomarkers. Biomolecules 12 (6), 824. doi:10.3390/biom12060824
Olas, B. (2023). Cardioprotective potential of berries of Schisandra chinensis turcz. (baill.), their components and food products. Nutrients 15 (3), 592. doi:10.3390/nu15030592
Ortiz, A. C., Fideles, S. O. M., Reis, C. H. B., Bellini, M. Z., Pereira, ESBM, Pilon, J. P. G., et al. (2022). Therapeutic effects of citrus flavonoids neohesperidin, hesperidin and its aglycone, hesperetin on bone health. Biomolecules 12 (5), 626. doi:10.3390/biom12050626
Palomer, X., Wang, J. R., Escalona, C., Wu, S., Wahli, W., and Vázquez-Carrera, M. (2025). Targeting AMPK as a potential treatment for hepatic fibrosis in MASLD. Trends Pharmacol. Sci. 46 (6), 551–566. doi:10.1016/j.tips.2025.03.008
Piao, Y., Jin, J., Zhou, D., and Quan, H. (2022). Mechanism of eugenol improving nonalcoholic fatty liver disease through AMPK and SREBP1 pathways. Chin J Tradit Chin Med. 37 (02), 1102–1106.
Powell, E. E., Wong, V. W., and Rinella, M. (2021). Non-alcoholic fatty liver disease. Lancet 397 (10290), 2212–2224. doi:10.1016/S0140-6736(20)32511-3
Pyun, D. H., Kim, T. J., Park, S. Y., Lee, H. J., Abd El-Aty, A. M., Jeong, J. H., et al. (2021). Patchouli alcohol ameliorates skeletal muscle insulin resistance and NAFLD via AMPK/SIRT1-mediated suppression of inflammation. Mol. Cell Endocrinol. 538, 111464. doi:10.1016/j.mce.2021.111464
Ren, Q., Sun, Q., and Fu, J. (2024a). Dysfunction of autophagy in high-fat diet-induced non-alcoholic fatty liver disease. Autophagy 20 (2), 221–241. doi:10.1080/15548627.2023.2254191
Ren, L., Wang, R., Wang, Y., Tie, F., Dong, Q., Wang, H., et al. (2024b). Exploring the effect and mechanism of Hippophae rhamnoides L. triterpenoid acids on improving NAFLD based on network pharmacology and experimental validation in vivo and in vitro. J. Ethnopharmacol. 335, 118657. doi:10.1016/j.jep.2024.118657
Rinella, M. E., Lazarus, J. V., Ratziu, V., Francque, S. M., Sanyal, A. J., Kanwal, F., et al. (2023). A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology 78 (6), 1966–1986. doi:10.1097/HEP.0000000000000520
Salimo, Z. M., Yakubu, M. N., da Silva, E. L., de Almeida, A. C. G., Chaves, Y. O., Costa, E. V., et al. (2023). Chemistry and pharmacology of bergenin or its derivatives: a promising molecule. Biomolecules 13 (3), 403. doi:10.3390/biom13030403
Sangpairoj, K., Pranweerapaiboon, K., Saengkhae, C., Meemon, K., Niamnont, N., Tamtin, M., et al. (2024). Extracts of tropical green seaweed Caulerpa lentillifera reduce hepatic lipid accumulation by modulating lipid metabolism molecules in HepG2 cells. Heliyon 10 (6), e27635. doi:10.1016/j.heliyon.2024.e27635
Shamsabadi, S., Nazer, Y., Ghasemi, J., Mahzoon, E., Baradaran Rahimi, V., Ajiboye, B. O., et al. (2023). Promising influences of zingerone against natural and chemical toxins: a comprehensive and mechanistic review. Toxicon 233, 107247. doi:10.1016/j.toxicon.2023.107247
Sharma, A., Anand, S. K., Singh, N., Dwarkanath, A., Dwivedi, U. N., and Kakkar, P. (2021). Berbamine induced activation of the SIRT1/LKB1/AMPK signaling axis attenuates the development of hepatic steatosis in high-fat diet-induced NAFLD rats. Food Funct. 12 (2), 892–909. doi:10.1039/d0fo02501a
Shen, B., Feng, H., Cheng, J., Li, Z., Jin, M., Zhao, L., et al. (2020). Geniposide alleviates non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signalling pathways. J. Cell Mol. Med. 24 (9), 5097–5108. doi:10.1111/jcmm.15139
Shen, Q., Chen, Y., Shi, J., Pei, C., Chen, S., Huang, S., et al. (2023a). Asperuloside alleviates lipid accumulation and inflammation in HFD-Induced NAFLD via AMPK signaling pathway and NLRP3 inflammasome. Eur. J. Pharmacol. 942, 175504. doi:10.1016/j.ejphar.2023.175504
Shen, B., Wang, Y., Cheng, J., Peng, Y., Zhang, Q., Li, Z., et al. (2023b). Pterostilbene alleviated NAFLD via AMPK/mTOR signaling pathways and autophagy by promoting Nrf2. Phytomedicine 109, 154561. doi:10.1016/j.phymed.2022.154561
Sheu, M. J., Yeh, M. C., Tsai, M. C., Wang, C. C., Chang, Y. L., Wang, C. J., et al. (2023). Glucosinolates extracts from Brassica juncea ameliorate HFD-induced non-alcoholic steatohepatitis. Nutrients 15 (16), 3497. doi:10.3390/nu15163497
Shi, Y., Chen, J., Qu, D., Sun, Q., Yu, Y., Zhang, H., et al. (2024). Ginsenoside Rg5 activates the LKB1/AMPK/mTOR signaling pathway and modifies the gut microbiota to alleviate nonalcoholic fatty liver disease induced by a high-fat diet. Nutrients 16 (6), 842. doi:10.3390/nu16060842
Singh, P., Arif, Y., Bajguz, A., and Hayat, S. (2021). The role of quercetin in plants. Plant Physiol. Biochem. 166, 10–19. doi:10.1016/j.plaphy.2021.05.023
Smiles, W. J., Ovens, A. J., Oakhill, J. S., and Kofler, B. (2024). The metabolic sensor AMPK: twelve enzymes in one. Mol. Metab. 90, 102042. doi:10.1016/j.molmet.2024.102042
Steinberg, G. R., and Hardie, D. G. (2023). New insights into activation and function of the AMPK. Nat. Rev. Mol. Cell Biol. 24 (4), 255–272. doi:10.1038/s41580-022-00547-x
Steinberg, G. R., Valvano, C. M., De Nardo, W., and Watt, M. J. (2025). Integrative metabolism in MASLD and MASH: pathophysiology and emerging mechanisms. J. Hepatol. 83 (2), 584–595. doi:10.1016/j.jhep.2025.02.033
Tan, H., Mi, N., Tong, F., Zhang, R., Abudurexiti, A., Lei, Y., et al. (2024). Lactucopicrin promotes fatty acid β-oxidation and attenuates lipid accumulation through adenosine monophosphate-activated protein kinase activation in free fatty acid-induced human hepatoblastoma cancer cells. Food Sci. Nutr. 12 (8), 5357–5372. doi:10.1002/fsn3.4176
Trefts, E., and Shaw, R. J. (2021). AMPK: restoring metabolic homeostasis over space and time. Mol. Cell 81 (18), 3677–3690. doi:10.1016/j.molcel.2021.08.015
Wang, S. W., Lan, T., Chen, H. F., Sheng, H., Xu, C. Y., Xu, L. F., et al. (2022a). Limonin, an AMPK activator, inhibits hepatic lipid accumulation in high fat diet fed mice. Front. Pharmacol. 13, 833705. doi:10.3389/fphar.2022.833705
Wang, D., Cao, L., Zhou, X., Wang, G., Ma, Y., Hao, X., et al. (2022b). Mitigation of honokiol on fluoride-induced mitochondrial oxidative stress, mitochondrial dysfunction, and cognitive deficits through activating AMPK/PGC-1α/Sirt3. J. Hazard Mater. 437, 129381. doi:10.1016/j.jhazmat.2022.129381
Wang, Z., Wang, Y., Zhang, C., Yuan, F., Xu, T., Zhu, M., et al. (2023a). Protective effect of corosolic acid on mice nonalchoholic fatty liver disease induced by high fat diet and its mechanism. J Med Sci Yanbian Univ. 46 (02), 103–106. doi:10.16068/j.1000-1824.2023.02.004
Wang, J., Du, H., Chen, M., Cao, H., Tong, N., Ye, M., et al. (2023b). Corilagin protects non-alcoholic fatty liver disease in mice induced by high fat and high sugar diet via regulating AMPK-Autophagy signaling. Chin. Pharmacol. Bull. 39 (09), 1725–1730. doi:10.12360/CPB202305046
Wang, C., Feng, X., Li, W., Chen, L., Wang, X., Lan, Y., et al. (2024a). Apigenin as an emerging hepatoprotective agent: current status and future perspectives. Front. Pharmacol. 15, 1508060. doi:10.3389/fphar.2024.1508060
Wang, C., Yang, F., Zeng, W., Chen, X., Qiu, Z., Wang, Q., et al. (2024b). Vine tea total flavonoids activate the AMPK/mTOR pathway to amelioration hepatic steatosis in mice fed a high-fat diet. J. Food Sci. 89 (5), 3019–3036. doi:10.1111/1750-3841.17025
Wang, T., Gao, L., Tan, J., Zhuoma, D., Yuan, R., Li, B., et al. (2024c). The neuroprotective effect of sophocarpine against glutamate-induced HT22 cell cytotoxicity. J. Oleo Sci. 73 (3), 359–370. doi:10.5650/jos.ess23089
Winarto, J., Song, D. G., and Pan, C. H. (2023). The role of fucoxanthin in non-alcoholic fatty liver disease. Int. J. Mol. Sci. 24 (9), 8203. doi:10.3390/ijms24098203
Wu, J. M., Zhaori, G., Mei, L., Ren, X. M., Laga, A. T., and Deligen, B. (2023a). Plantamajoside modulates immune dysregulation and hepatic lipid metabolism in rats with nonalcoholic fatty liver disease via AMPK/Nrf2 elevation. Kaohsiung J. Med. Sci. 39 (8), 801–810. doi:10.1002/kjm2.12712
Wu, D., Yang, Q., Xie, G., and Peng, X. (2023b). Effect of daidzein on autophagy in rats with non-alcoholic fatty liver disease by regulating SIRT1/AMPK signaling pathway. Int. J Lab Med 44 (19), 2395–2401. doi:10.3969/ji.ssn.1673-4130.2023
Wu, Y., Xiong, J., Chen, G., Liu, Y., Zhao, C., Zhang, Z., et al. (2025). Oxymatrine relieves non-alcoholic fatty liver disease by promoting sirtuin 1/adenosine 5'-monophosphate-activated protein kinase pathway and peroxisome proliferator activated receptor alpha-mediated hepatic fatty acid oxidation. Eur. J. Pharmacol. 987, 177173. doi:10.1016/j.ejphar.2024.177173
Xiang, G., Guo, S., Xing, N., Du, Q., Qin, J., Gao, H., et al. (2024). Mangiferin, a potential supplement to improve metabolic syndrome: current status and future opportunities. Am. J. Chin. Med. 52 (2), 355–386. doi:10.1142/S0192415X24500150
Xiao, T., Cui, Y., Ji, H., Yan, L., Pei, D., and Qu, S. (2021). Baicalein attenuates acute liver injury by blocking NLRP3 inflammasome. Biochem. Biophys. Res. Commun. 534, 212–218. doi:10.1016/j.bbrc.2020.11.109
Xie, L., Yuan, Y., Xu, S., Lu, S., Gu, J., Wang, Y., et al. (2022). Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex. Cell Rep. 41 (3), 111498. doi:10.1016/j.celrep.2022.111498
Xu, Q. Q., Su, Z. R., Yang, W., Zhong, M., Xian, Y. F., and Lin, Z. X. (2023a). Patchouli alcohol attenuates the cognitive deficits in a transgenic mouse model of alzheimer's disease via modulating neuropathology and gut microbiota through suppressing C/EBPβ/AEP pathway. J. Neuroinflammation 20 (1), 19. doi:10.1186/s12974-023-02704-1
Xu, H., Yu, H., Fu, J., Zhang, Z. W., Hu, J. C., Lu, J. Y., et al. (2023b). Metabolites analysis of plantamajoside based on gut microbiota-drug interaction. Phytomedicine 116, 154841. doi:10.1016/j.phymed.2023.154841
Xu, J., Jia, W., Zhang, G., Liu, L., Wang, L., Wu, D., et al. (2024). Extract of Silphium perfoliatum L. improve lipid accumulation in NAFLD mice by regulating AMPK/FXR signaling pathway. J. Ethnopharmacol. 327, 118054. doi:10.1016/j.jep.2024.118054
Yan, L. S., Zhang, S. F., Luo, G., Cheng, B. C., Zhang, C., Wang, Y. W., et al. (2022). Schisandrin B mitigates hepatic steatosis and promotes fatty acid oxidation by inducing autophagy through AMPK/mTOR signaling pathway. Metabolism 131, 155200. doi:10.1016/j.metabol.2022.155200
Yang, Z., Zhang, L., Liu, J., Chan, A. S. C., and Li, D. (2023). Saponins of tomato extract improve non-alcoholic fatty liver disease by regulating oxidative stress and lipid homeostasis. Antioxidants (Basel) 12 (10), 1848. doi:10.3390/antiox12101848
Yao, P., and Liu, Y. (2022). Terpenoids: natural compounds for non-alcoholic fatty liver disease (NAFLD) therapy. Molecules 28 (1), 272. doi:10.3390/molecules28010272
Ye, J., Zheng, J., Tian, X., Xu, B., Yuan, F., Wang, B., et al. (2022). Fucoxanthin attenuates free fatty acid-induced nonalcoholic fatty liver disease by regulating lipid metabolism/oxidative stress/inflammation via the AMPK/Nrf2/TLR4 signaling pathway. Mar. Drugs 20 (4), 225. doi:10.3390/md20040225
Yi, M., Fasina, O. B., Li, Y., Xiang, L., and Qi, J. (2023). Mixture of peanut skin extract, geniposide, and isoquercitrin improves the hepatic lipid accumulation of mice via modification of gut microbiota homeostasis and the TLR4 and AMPK signaling pathways. Int. J. Mol. Sci. 24 (23), 16684. doi:10.3390/ijms242316684
Yong, Z., Ruiqi, W., Hongji, Y., Ning, M., Chenzuo, J., Yu, Z., et al. (2021). Mangiferin ameliorates HFD-induced NAFLD through regulation of the AMPK and NLRP3 inflammasome signal pathways. J. Immunol. Res. 2021, 4084566. doi:10.1155/2021/4084566
You, L., Wang, T., Li, W., Zhang, J., Zheng, C., Zheng, Y., et al. (2024). Xiaozhi formula attenuates non-alcoholic fatty liver disease by regulating lipid metabolism via activation of AMPK and PPAR pathways. J. Ethnopharmacol. 329, 118165. doi:10.1016/j.jep.2024.118165
Zhang, J., Ma, X., and Fan, D. (2022a). Ginsenoside CK ameliorates hepatic lipid accumulation via activating the LKB1/AMPK pathway in vitro and in vivo. Food Funct. 13 (3), 1153–1167. doi:10.1039/d1fo03026d
Zhang, Y., Yin, R., Lang, J., Fu, Y., Yang, L., and Zhao, D. (2022b). Epigallocatechin-3-gallate ameliorates hepatic damages by relieve FGF21 resistance and promotion of FGF21-AMPK pathway in mice fed a high fat diet. Diabetol. Metab. Syndr. 14 (1), 53. doi:10.1186/s13098-022-00823-y
Zhang, J., Zhang, W., Yang, L., Zhao, W., Liu, Z., Wang, E., et al. (2023a). Phytochemical gallic acid alleviates nonalcoholic fatty liver disease via AMPK-ACC-PPARa axis through dual regulation of lipid metabolism and mitochondrial function. Phytomedicine 109, 154589. doi:10.1016/j.phymed.2022.154589
Zhang, W., Chen, H., Xu, Z., Zhang, X., Tan, X., He, N., et al. (2023b). Liensinine pretreatment reduces inflammation, oxidative stress, apoptosis, and autophagy to alleviate sepsis acute kidney injury. Int. Immunopharmacol. 122, 110563. doi:10.1016/j.intimp.2023.110563
Zhang, L. J., Li, S. Y., Fan, S. L., Nuerbiye, A., Zhao, J. Y., Keremu, B., et al. (2025a). Hepatoprotective activity of mulberry extract in NAFLD mice for regulating lipid metabolism and inflammation identified via AMPK/PPAR-γ/NF-κB axis. J. Ethnopharmacol. 351, 120108. doi:10.1016/j.jep.2025.120108
Zhang, G., Jia, W., Liu, L., Wang, L., Xu, J., Tao, J., et al. (2025b). Caffeoylquinic acids from Silphium perfoliatum L. show hepatoprotective effects on cholestatic mice by regulating enterohepatic circulation of bile acids. J. Ethnopharmacol. 337 (Pt 2), 118870. doi:10.1016/j.jep.2024.118870
Zhao, J., Zhou, H., An, Y., Shen, K., and Yu, L. (2021). Biological effects of corosolic acid as an anti-inflammatory, anti-metabolic syndrome and anti-neoplasic natural compound. Oncol. Lett. 21 (2), 84. doi:10.3892/ol.2020.12345
Zhu, Y., Liu, R., Shen, Z., and Cai, G. (2020). Combination of luteolin and lycopene effectively protect against the “two-hit” in NAFLD through Sirt1/AMPK signal pathway. Life Sci. 256, 117990. doi:10.1016/j.lfs.2020.117990
Keywords: traditional Chinese medicine, AMPK signaling pathway, non-alcoholic fatty liver disease, mechanism, lipid accumulation
Citation: Zhang C, Shi J and Shi L (2025) Natural products intervene in non-alcoholic fatty liver disease by regulating the AMPK signaling pathway: preclinical evidence and mechanism. Front. Pharmacol. 16:1696506. doi: 10.3389/fphar.2025.1696506
Received: 02 September 2025; Accepted: 12 November 2025;
Published: 26 November 2025.
Edited by:
Javier Echeverria, University of Santiago, ChileReviewed by:
Kwazi Gabuza, South African Medical Research Council, South AfricaZheng Xu, The Seventh Clinical Medical College of Guangzhou University of Chinese Medicine, China
Copyright © 2025 Zhang, Shi and Shi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lijun Shi, c2hpbGlqdW4yMDA4MjAyMUAxNjMuY29t