Li Zhang, Jianhua Li, Huilu Zhang, Qi Qin, Yichen Huang, Xiaofan Tian, Chao Sun, Binbin Li, Zhengxin Wang, Xin Zhang
Despite extensive research, the etiology of metabolic dysfunction-associated steatotic liver disease (MASLD) remains incompletely understood. Through analysis of single-cell RNA sequencing (scRNA-seq) data from murine and human MASLD models, we identify a lipid-associated hepatocyte population and implicate Rab1A as its prominent player. Both global knockout and liver-specific knockdown of Rab1A mitigate western diet-induced hepatic steatosis in adult mice. We further show that knockdown of Rab1A in hepatic cells attenuates lipid accumulation by inducing excessive mitophagy. Mechanistically, Rab1A suppresses Raf-1 activation, thereby inhibiting the MEK/ERK1/2 signaling cascade. Pharmacological inhibition of MEK/ERK1/2 via U0126 reverses lipid depletion and restores mitophagy attenuation in Rab1A-deficient cells. We further demonstrate that ERK1/2 directly interacts with and phosphorylates PINK1 at Ser228, triggering PINK1-Parkin-dependent mitophagy. Critically, pharmacological activation of mitophagy by Urolithin A, or by C16-PAF used as a research tool to engage the ERK1/2/PINK1-Parkin axis, alleviates high-fat diet-induced hepatic steatosis and attenuates MASLD progression in mice. In human MASLD patients, Rab1A expression inversely correlates with activation of the Raf-1/ERK1/2/PINK1 pathway. Collectively, our findings identify the Rab1A/Raf-1/ERK1/2/PINK1 axis as a key regulator of mitophagy and MASLD pathogenesis, and highlight this pathway as a promising target for future therapeutic development.