Liver fibrosis affects hundreds of millions of people globally and currently lacks approved pharmacological treatments capable of reversing established scarring. A growing body of mechanistic work is reframing the condition not merely as a wound-healing excess but as a failure of cellular quality control — specifically, the selective recycling of damaged mitochondria known as mitophagy.
This review in Acta Pharmacologica Sinica synthesizes evidence that impaired mitophagy is a convergent mechanism across the major fibrogenic cell types — hepatic stellate cells, hepatocytes, and macrophages — driving fibrosis through accumulation of dysfunctional mitochondria, amplified oxidative stress, and sustained inflammatory signaling. The authors map key mitophagic pathways implicated in this process, including PINK1/Parkin-dependent receptor-mediated routes such as BNIP3 and NIX, and examine how their dysregulation licenses stellate cell activation, the central cellular event in fibrogenesis. Several candidate compounds that modulate these pathways are evaluated as potential therapeutic targets.
What makes this analysis particularly timely is the recent clinical momentum around mitochondria-targeting strategies in metabolic liver disease. MASH (metabolic dysfunction-associated steatohepatitis) has overtaken viral hepatitis as the dominant fibrosis etiology in high-income countries, and mitochondrial dysfunction is now recognized as an early and persistent feature of its pathophysiology. Situating mitophagy at the intersection of oxidative damage, inflammasome activation, and stellate cell fate gives this framework translational weight. That said, reviews of this type carry inherent limitations: the causal hierarchy among these pathways in human tissue remains incompletely established, most supporting data derive from rodent models or in vitro systems, and selective mitophagy induction risks unintended effects on hepatocyte viability. The field needs well-powered human biopsy studies correlating mitophagic flux markers with fibrosis stage to validate these targets. This represents a thoughtful synthesis rather than a paradigm shift, but it meaningfully advances the mechanistic rationale for pursuing mitophagy modulators in a disease space with few therapeutic options.