Genetic or pharmacological inhibition of hepatic TMEM141 attenuates MASH and fibrosis via the ROS-HNF4α signaling pathway.

Metabolic dysfunction-associated steatoic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), have become a global epidemic due to obesity and genetic susceptibility. Here, we report transmembrane protein 141 (TMEM141), a protein with a largely unknown function, as a key regulator of MASH and MASH-associated fibrosis. Hepatic TMEM141 is reduced in MASLD/MASH patients and mouse models of MASLD/MASH due to increased microRNA-149. Unexpectedly, genetic inactivation of hepatocyte TMEM141 protects against MASLD/MASH induced by a high fat/cholesterol/fructose (HFCF) diet, whereas hepatic overexpression of human TMEM141 exacerbates MASLD/MASH. We further show that TMEM141 localizes within mitochondria and interacts with mitochondrial complex I to regulate ROS production. Inactivation of TMEM141 reduces ROS production, induces hepatocyte nuclear factor 4α (HNF4α), and fails to protect against HFCF diet-induced MASH or fibrosis in the absence of hepatocyte HNF4α. Finally, pharmacological inhibition of hepatic TMEM141 by N-acetylgalactosamine (GalNAc)-siTmem141 significantly promotes the reversal of HFCF diet-induced MASH and fibrosis. These findings underscore a critical role of TMEM141 in MASH development and suggest that targeting hepatic TMEM141 may represent a promising strategy for treating MASH and MASH-associated fibrosis.