Unveiling the cellular and molecular mechanisms of traditional Chinese medicine in hepatic fibrosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatic fibrosis (HF) is a prevalent consequence of chronic liver injury, resulting from the persistent interplay of inflammation, oxidative stress, dysregulated cell death, metabolic reprogramming, and remodeling of the immune microenvironment, which collectively establish a self-amplifying profibrotic network. In traditional medical systems, HF corresponds to syndromes such as hypochondriac pain, mass formation, blood stasis, and jaundice, indicating a chronic and systemically imbalanced disease trajectory. Guided by holistic and multi-target principles, traditional Chinese medicine (TCM) has amassed considerable ethnopharmacological knowledge in managing chronic liver diseases and fibrosis.

AIM OF THE STUDY: This review seeks to transcend single-mechanism explanations by integrating contemporary evidence regarding the antifibrotic effects of TCM from a systems-pathology perspective. We aim to elucidate how TCM interventions coordinately modulate the interactions among inflammation, oxidative stress, programmed cell death, metabolic dysregulation, and remodeling of the immune microenvironment, thereby disrupting the self-sustaining fibrotic network.

MATERIALS AND METHODS: Bibliometric analyses were performed to characterize research trends and thematic evolution in TCM-related antifibrotic studies. Concurrently, a systematic literature search was executed in PubMed, Web of Science, and CNKI for experimental and clinical studies published between 2000 and 2025. The Latin binomials of all medicinal plants discussed were standardized and verified using the Medicinal Plant Names Services (MPNS) database to ensure taxonomic accuracy and nomenclatural consistency.

RESULTS: Current evidence suggests that TCM does not exert antifibrotic effects by targeting isolated pathological nodes; instead, it attenuates key profibrotic feedback loops through multi-level coordinated regulation. At the inflammatory level, TCM suppresses amplification axes centered on NF-κB and NLRP3, thereby diminishing the cumulative injury burden imposed by persistent immune activation on both parenchymal and non-parenchymal liver cells. At the levels of oxidative stress and metabolism, TCM modulates Nrf2-associated antioxidant networks in conjunction with energy and lipid metabolic pathways, disrupting the reciprocal reinforcement between oxidative stress and metabolic reprogramming. Regarding programmed cell death, TCM influences the dynamic balance among apoptosis, pyroptosis, necroptosis, and ferroptosis, thereby limiting the continuous pro-inflammatory stimulation of the fibrotic microenvironment. In terms of immune microenvironment remodeling, TCM regulates macrophage polarization, lymphocyte function, and sinusoidal endothelial phenotypes, facilitating a transition from a profibrotic state to reparative immune homeostasis. These convergent effects ultimately integrate at critical signaling nodes, including TGF-β/Smad, PI3K/Akt/mTOR, and Wnt/β-catenin pathways, thereby attenuating extracellular matrix accumulation and its associated mechanotransductive feedback that sustains fibrosis.

CONCLUSION: Collectively, TCM demonstrates a systems-level antifibrotic profile by modulating the interactions among multiple pathological processes, rather than relying solely on single-target inhibition. This mode of action is consistent with the complex pathophysiology of HF. However, current evidence primarily relies on associative mechanisms and phenotypic improvements, while offering limited insight into multicellular causal interactions, critical regulatory nodes, and the pharmacodynamic foundations of TCM interventions. Consequently, future research should conceptualize HF as a disorder characterized by disrupted inter-organ regulation, integrate the gut-liver axis and immune involvement, employ single-cell and multi-omics approaches to elucidate causal pathways, and validate system-level effects through rigorously designed long-term clinical studies.