Abstract / Summary
ABSTRACT 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.