Mitophagy is selective degrade the damaged or unnecessary mitochondria by autophagy. Parkin is a key molecule regulating mitophagy along with PINK1. In this study, we explored the role of mitophagy and its regulatory mechanism in HSC activation. We found that Parkin exists abundantly in HSCs than in hepatocytes. In addition, we observed that parkin expression was increased in mouse or human fibrotic liver tissue. Parkin was also increased in LX-2 cells treated with TGF-β or in primary HSC from mouse liver injected with CCL4. We found that TGF-β-induced Parkin expression was regulated by transcriptionally and post-transcriptionally mechanism. TGF-β treatment did not affect the mitochondrial function, but activated autophagy. Autophagy was inhibited by Mdivi-1 and actually increased in the mitochondrial fraction, proving that Parkin was transferred to the mitochondria. Collectively, we found that Parkin, induced by TGF-β, does not affect mitochondrial function in HSC, but promotes HSC activation by contributing to the maintenance of mitochondrial homeostasis through mitophagy. (NRF-RS-2023-00222390)