Targeting the E3 ubiquitin ligase RNF10 ameliorates metabolic dysfunction-associated steatohepatitis in mice

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a global health concern. Nevertheless, its underlying pathological mechanisms remain poorly understood. Here, we showed that E3 ubiquitin ligase ring finger protein 10 (RNF10) protein levels were positively correlated with MASLD in both mice and humans. Hepatic-specific Rnf10 deletion attenuated liver steatosis, inflammation, and fibrosis. Conversely, adeno-associated virus (AAV)-mediated hepatic-specific Rnf10 overexpression exacerbated MASLD-related phenotypes. Mechanistically, RNF10 interacted with carnitine palmitoyltransferase 1A (CPT1A) and facilitated its degradation through K48-linked ubiquitination, thereby inhibiting fatty acid oxidation, promoting hepatic lipid accumulation, and ultimately exacerbating liver inflammation and fibrosis. Moreover, we utilized triantennary N-acetylgalactosamine (GalNAc) to deliver small interfering RNA (siRNA) specifically targeting Rnf10 to hepatocytes. This approach effectively ameliorated diet-induced liver steatosis, inflammation, and fibrosis in mice. Therefore, interfering with the expression or function of RNF10 may be a promising therapeutic strategy for MASLD.

Authors

Chunyuan Du, Yinliang Zhang, Hongkai Chang, Chaofan Xu, Sufang Sheng, Ke Xu, Wei Qiao, Yanjun Liu, Tongtong Zhang, Yong Gao, Peng Li, Yongsheng Chang