Aug 2026· Frontiers in Pharmacology· Vol 17· 0 citations· 117 references
Medicine
TL;DR
It is suggested that selected phytochemicals associated with TCM herbs may modulate immunometabolic processes involved in liver fibrosis, but their therapeutic potential remains incompletely defined and requires confirmation in standardized, mechanistically informed clinical studies.
Abstract
Liver fibrosis is a progressive consequence of chronic hepatic injury characterized by sustained activation of hepatic stellate cells (HSCs) within a complex network of metabolic and inflammatory signaling. This review critically examines selected plant-derived metabolites associated with herbs used in Traditional Chinese Medicine (TCM), including salvianolic acid B, curcumin, berberine, resveratrol, puerarin, glycyrrhizin, tetrandrine, oroxylin A, and schisandrin B, for their potential roles in modulating immunometabolic pathways relevant to fibrogenesis. A structured search of PubMed and Web of Science identified mechanistic, preclinical, and clinical studies. Overall, these compounds were reported to influence key pathways implicated in liver fibrogenesis, including glycolysis, mitochondrial dysfunction, lipid metabolism, NF-κB, TGF-β/Smad, PI3K–Akt–mTOR, and HIF-1α signaling. However, the strength of evidence varies considerably across compounds. Curcumin and resveratrol have the most consistent translational data, whereas salvianolic acid B, tetrandrine, and oroxylin A remain supported primarily by preclinical findings with limited mechanistic and clinical validation. Current evidence is constrained by model heterogeneity, reliance on associative pathway analyses, and the scarcity of histologically confirmed clinical outcomes. These findings suggest that selected phytochemicals associated with TCM herbs may modulate immunometabolic processes involved in liver fibrosis, but their therapeutic potential remains incompletely defined and requires confirmation in standardized, mechanistically informed clinical studies.
Background:Liver fibrosis is a progressive pathological process that is the super-accumulation of extracellular matrix (ECM) due to chronic liver damage. Dysregulated signaling pathways involving interleukin-6 (IL-6), epidermal growth factor receptor (EGFR), and protein kinase B (AKT1), are implicated in hepatic stellate cell (HSC) activation, fibrogenesis, and progression toward cirrhosis and hepatocellular carcinoma (HCC). Despite advances in understanding these mechanisms, effective pharmacological interventions with favorable safety profiles remain limited. Methods:The current research examined the effects of two naturally occurring flavonoids, Kaempferol and Coumestrol on fibrosis-linked oncogenic signaling using an integrated in silico and in vitro study. Molecular docking studies were conducted to assess the binding affinities and the interaction profiles of both compounds with IL-6, EGFR, AKT1, and Caspase-3 (CASP3). Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling was used to predict pharmacokinetic and toxicity properties to evaluate drug-likeness and safety parameters. In vitro experiments were conducted in HepG2 and Huh7 hepatocellular carcinoma cell lines to evaluate cytotoxicity, cell viability, migration, invasion, colony formation, and expression of IL-6, EGFR, AKT1, and Caspase-3. IC50 values were derived from dose-response curves generated from three independent technical experimental replicates.Results:Docking analysis showed stable binding interactions of both compounds at the active sites of IL-6, EGFR, AKT1, and CASP3, supported by hydrogen bonding and hydrophobic interactions, and ADMET predictions indicated favorable absorption with manageable toxicity profiles. In HepG2 and Huh7 cells, Kaempferol and Coumestrol showed dose-dependent reductions in cell viability, migration, invasion, and colony formation, along with downregulation of EGFR, AKT1, and IL-6 and upregulation of Caspase-3 at the transcript level. Conclusion: These findings suggest that Kaempferol and Coumestrol modulate IL-6/EGFR/AKT1-associated oncogenic signaling in hepatocellular carcinoma cells in vitro, indicating possible relevance to fibrosis-to-HCC progression. However, this study did not directly assess hepatic stellate cell activation or classical fibrogenic markers, and further studies using HSC models and in vivo validation are needed to confirm anti-fibrotic potential.
Unknown authors· International Journal of Pha...· 0 citations
Hepatic fibrosis is a pivotal pathological stage in chronic liver disease progression for which treatment options remain limited. Medicinal-food homologous (MFH) plants, recognized for their dual safety and bioactivity, offer promising preventive and therapeutic potential. This review systematically analyzes the anti-hepatofibrotic mechanisms of 102 officially approved MFH plants. Based on a literature search using keywords such as “specific MFH plant names” and “hepatic fibrosis or liver fibrosis,” we identified 101 relevant studies. The analysis reveals that these plants exert their effects through multi-target synergy, mitigating oxidative stress and inflammation, inhibiting hepatic stellate cell (HSC) activation, inducing activated HSC apoptosis, and modulating the gut-liver axis. Although bioactive compounds such as hesperetin, puerarin, and curcumin have emerged as prominent candidates for therapeutic intervention in hepatic fibrosis, related studies remain largely confined to the pre-clinical stage. Furthermore, approximately one-third of the evidence is derived from crude extracts with poorly characterized compositions; active compounds lack systematic pharmacokinetic and toxicological evaluations; clinical studies remain exceptionally limited; and experimental doses far exceed typical daily dietary intake levels. These limitations severely compromise their clinical translation and application value. Future research should focus on elucidating the mechanisms of single active compounds, establishing long-term intervention models using physiologically relevant doses, and conducting high-quality randomized controlled trials, thereby facilitating the translation of MFH plants from dietary prevention to clinical therapy.
Shiqi Chen, Hongda Chen, Jiaqi Xie et al.· Frontiers in Nutrition· 0 citations
Liver fibrosis, a severe chronic liver injury sequela, lacks effective therapies. Quercetin, a natural flavonoid, exhibits multi-target anti-fibrotic potential.
This study integrated network pharmacology,metabolomics, molecular docking, and molecular dynamics simulations to investigate its mechanisms.
Network analysis identified 203 overlapping targets, with core targets including protein kinase B (AKT1), interleukin-6 (IL6), tumor protein p53 (TP53), and tumor necrosis factor (TNF), which were enriched in PI3K-Akt and TNF signaling pathways. In CCl4- induced rats (quercetin 50 mg/kg/day), quercetin alleviated pathological damage, significantly reduced collagen area by 43.1% (P = 0.006), and lowered serum alanine aminotransferase, aspartate aminotransferase, and type III procollagen levels. Metabolomics revealed 32 differential metabolites, implicating multiple metabolic pathways including lipid and amino acid metabolism. Molecular docking showed strong binding to AKT1 (5.8 kcal/mol) and TNF (7.2 kcal/ mol), with stable complexes over 100 ns simulations. QPCR was used to detect the expression of PI3K/AKT1 core targets in liver tissue, and experimental verification confirmed the predicted key targets.
This multi-faceted study elucidates quercetin’s anti-fibrotic mechanism, laying a foundation for its therapeutic development.
Xiaowen Song, Tian-Fu Guo, Ya-Xin Li et al.· Frontiers in Pharmacology· 0 citations
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive immunometabolic liver disorder involving lipid dysregulation, inflammation, fibrosis, and extrahepatic immune–neural responses, yet therapies capable of modulating these interconnected processes remain limited. Berberine (BBR), an isoquinoline alkaloid derived from traditional medicinal plants including Coptis chinensis Franch. (Coptidis Rhizoma), has shown metabolic and anti-inflammatory activities; however, its effects on hepatic inflammation and the liver–brain inflammatory axis in MASH remain unclear. Here, network pharmacology and molecular docking were used to predict BBR targets and pathways, followed by in vivo validation in a methionine- and choline-deficient diet-induced mouse model. Liver injury and metabolic alterations were assessed using serum biochemistry and lipid profiles, histological changes by hematoxylin and eosin and Sirius Red staining, and hepatic and hypothalamic inflammation by qRT-PCR, flow cytometry, and Iba-1/GFAP immunostaining. SREBF1, AKT1, and TGFB1 were identified as core BBR targets, with pathways linked to lipid metabolism, oxidative stress, inflammation, and fibrogenesis. BBR attenuated liver injury, steatosis, steatohepatitis, and fibrosis, suppressed SREBF1-associated lipogenic signaling and fibrogenic gene expression, remodeled circulating monocyte subsets, reduced Kupffer cell accumulation, and inhibited hypothalamic microglial activation. These findings suggest that BBR alleviates MCD-induced steatohepatitis through multi-target regulation of hepatic metabolic dysfunction, immune remodeling, and hypothalamic neuroinflammation.
Yeon-Joo Yoo, Jihan Kim, Seunghoon Yoo et al.· International Journal of Mol...· 0 citations
This review summarizes recent advances in the use of natural products for the treatment of renal fibrosis, with a particular focus on their underlying molecular mechanisms, current status of clinical translation, and the challenges that remain.
Yan Liu, Lei Gao, Hao Xu et al.· Renal Failure· 0 citations
Hepatic fibrosis is a prevalent outcome of chronic liver diseases. Although activation of hepatic stellate cell (HSC) is a primary driver of fibrogenesis, therapeutic strategies targeting retinoic acid (RA) metabolism in HSCs remain insufficiently investigated. This study aimed to elucidate the material basis of Huanggen formula (FHG), identify its principal bioactive constituents, and clarify the underlying antifibrotic mechanisms. The antifibrotic efficacy of FHG was assessed in a CCl4-induced mouse model. Widely-targeted and untargeted metabolomics were conducted to characterize FHG constituents and serum-absorbed components, followed by high-content screening to evaluate anti-HSC activation activity. Rhein was further examined in TGF-β1-stimulated LX-2 cells and CCl4-induced mice. Label-free proteomics, multiple reaction monitoring quantification, DARTS, CETSA, and molecular docking were performed to identify the molecular targets of rhein. ALDH1A3 inhibition, knockdown, and overexpression were employed to verify its functional role in LX-2 cells. FHG markedly alleviated metabolic disturbances and histopathological injury in fibrotic mice. Metabolomic analysis identified anthraquinones and flavonoids as the principal active classes, with rhein exhibiting potent anti-HSC activation effects. Rhein suppressed LX-2 activation, extracellular matrix (ECM) accumulation, and migration, and mitigated CCl4-induced hepatic fibrosis. Proteomic analysis indicated that rhein regulated ECM remodeling, mitochondrial function, and RA metabolism, accompanied by significant upregulation of DHRS4 and ALDH1A3. Mechanistically, rhein directly targeted to ALDH1A3, enhanced its expression, and increased intracellular ATRA level. The inhibition of ALDH1A3 partially abrogated the effects of rhein. Knockdown and overexpression experiments verify that ALDH1A3 is a critical negative regulator of HSC activation. Rhein is a key antifibrotic constituent of FHG and suppresses hepatic fibrosis by targeting ALDH1A3 and restoring RA metabolism. The ALDH1A3-ATRA axis represents a central mechanism and a promising therapeutic target. Herb and serum metabolomics defined FHG’s chemical basis, highlighting anthraquinones. High-content screening identified rhein as the principal antifibrotic compound. Rhein suppressed HSC activation by through modulation of RA metabolism via ALDH1A3. Rhein upregulated ALDH1A3 and elevated ATRA level to inhibit HSC activation. The ALDH1A3-ATRA axis is critical for regulation of HSC activation. Herb and serum metabolomics defined FHG’s chemical basis, highlighting anthraquinones. High-content screening identified rhein as the principal antifibrotic compound. Rhein suppressed HSC activation by through modulation of RA metabolism via ALDH1A3. Rhein upregulated ALDH1A3 and elevated ATRA level to inhibit HSC activation. The ALDH1A3-ATRA axis is critical for regulation of HSC activation.
Kai Yu, Minqi Chen, Wanchao Hou et al.· Chinese Medicine· 0 citations
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