Advances in pharmacological interventions for hepatic fibrosis: from pathogenic mechanisms to novel therapeutic targets

Hepatic fibrosis (HF) is a pahological consequence of dysregulated wound healing, characterized by excessive deposition of extracellular matrix (ECM) that disrupts liver architecture and function.It is driven by diverse etiologies, including viral, metabolic, cholestatic and toxic insults. Additionally, the pathogenetic mechanisms progressing from initial injury to established fibrosis involve hepatocyte dysfunction, impaired autophagy, oxidative stress, immune modulation, and ultimately the activation of hepatic stellate cells, leading to a sustained imbalance between ECM synthesis and degradation. Consequently, developing effective therapies necessitates strategies targeting both specific etiologies and these core pathological mechanisms.This review systematically examines emerging anti-fibrotic strategies, spanning etiology-specific treatments and inhibitors targeting core pathways (e.g. stellate cell activation, oxidative stress). We evaluate investigational drugs ranging from small molecules and biologics to nano-formulations and highlight multi-targeting natural compounds from Traditional Chinese Medicine (TCM), such as silymarin and resveratrol, which modulate ECM remodeling, inflammation, and metabolism. By integrating preclinical and clinical evidence, this review provides a critical roadmap for developing synergistic therapies that combine modern targeted drugs with natural multi-target agents, addressing a key gap in current research on this integrative approach.