Emerging roles of mitophagy in liver fibrosis: Implications for therapy

Liver fibrosis, a pathological process characterized by excessive production of extracellular matrix (ECM) and sustained activation of hepatic stellate cells (HSCs), can further progress into cirrhosis and hepatocellular carcinoma. The disorder has imposed a heavy burden on global public health, resulting in millions of deaths annually. Mitophagy maintains mitochondrial function by eliminating dysfunctional mitochondria and regulating the biogenesis of new ones. It has been reported that mitophagy participates in the progression of liver diseases. However, the exact function of mitophagy in liver fibrosis remains unclear. In this review, we first outline the current knowledge regarding mitophagy regulatory mechanism. We then focus on the effect of mitophagy in the progression of liver fibrosis by regulating HSCs activation, oxidative stress, inflammatory signaling cascades, lipid metabolism reprogramming, and the modulation of the immune microenvironment. We further highlight that mitophagy mainly plays a protective role against liver fibrosis, whereas excessive mitophagy may exacerbate liver fibrosis by clearing healthy mitochondria aberrantly. Moreover, we summarize clinical data supporting mitophagy-targeted therapeutic strategies for liver fibrosis. Elucidation of these issues will offer new perspectives on the function of mitophagy during liver fibrosis, as well as potential strategies for anti-fibrotic therapy.