MAPK10 plays a protective role in NAFLD by ameliorating hepatic steatosis and mitochondrial dysfunction. Its expression is positively regulated by DNMT1 via m5C-mediated RNA stabilization. This study highlights the DNMT1-MAPK10 axis as a potential therapeutic target for NAFLD. Insight Box This study uncovers a previously unrecognized RNA epigenetic regulatory axis in NAFLD, demonstrating that DNMT1 post-transcriptionally regulates MAPK10 expression and stability through m5C RNA methylation. We establish MAPK10 as a key metabolic protector against NAFLD, ameliorating hepatic steatosis, oxidative stress, and mitochondrial dysfunction. By integrating bioinformatics, molecular biology, and functional validation across in vivo and in vitro models, we delineate a mechanistic pathway where m5C modification critically modulates MAPK10 activity. These findings not only provide fresh insight into the RNA-centric regulatory layer of NAFLD pathogenesis but also spotlight the therapeutic potential of modulating the DNMT1-MAPK10 axis, underscoring the value of integrative research strategies in elucidating complex metabolic diseases. Main points MAPK10 expression was significantly reduced in the liver tissues of HFD-induced NAFLD mice. MAPK10 overexpression alleviated hepatic steatosis and mitochondrial damage in HFD-fed mice. DNMT1 positively regulates MAPK10 expression and mRNA stability in an m5C RNA methylation-dependent manner.
Liu et al. (Thu,) studied this question.