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

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health issue with unclear mechanisms.
• Understanding the molecular drivers of MASLD is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of E3 ubiquitin ligase ring finger protein 10 (RNF10) in the pathogenesis of MASLD.
• To explore RNF10 as a potential therapeutic target for MASLD.

Main Methods:

• Correlation analysis of RNF10 levels with MASLD in mice and humans.
• Investigating the effects of hepatic RNF10 deletion and overexpression on MASLD phenotypes.
• Elucidating the molecular mechanism of RNF10 action, including its interaction with CPT1A and ubiquitination pathways.
• Utilizing GalNAc-siRNA delivery to target RNF10 in hepatocytes for therapeutic intervention.

Main Results:

• RNF10 protein levels positively correlate with MASLD severity in both murine models and human patients.
• Hepatic RNF10 deletion ameliorates MASLD, while overexpression exacerbates it.
• RNF10 targets CPT1A for degradation via K48-linked ubiquitination, inhibiting fatty acid oxidation and promoting lipid accumulation.
• GalNAc-siRNA mediated RNF10 knockdown effectively ameliorates diet-induced MASLD in mice.

Conclusions:

• RNF10 plays a critical role in promoting MASLD by disrupting fatty acid metabolism and driving liver pathology.
• Targeting RNF10, through methods like siRNA delivery, presents a promising therapeutic avenue for MASLD treatment.