RNF128 aggravates metabolic dysfunction-associated steatotic liver disease progression via stabilization of SCD1

Area of Science:

• Hepatology
• Molecular Biology
• Biochemistry

Background:

• Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive liver condition with complex pathology, hindering therapeutic development.
• Understanding the molecular drivers of MASLD progression is crucial for identifying effective treatment targets.

Purpose of the Study:

• To investigate the role of the E3 ubiquitin ligase RNF128 in the pathogenesis of MASLD.
• To elucidate the molecular mechanisms by which RNF128 influences MASLD progression.
• To evaluate the therapeutic potential of targeting the RNF128-SCD1 axis in MASLD.

Main Methods:

• Utilized diet-induced MASLD mouse models and bulk RNA-sequencing to analyze RNF128 expression.
• Characterized hepatic RNF128 expression using single-cell RNA sequencing and hepatocyte models.
• Assessed the impact of RNF128 modulation (knockout and overexpression) on MASLD phenotypes and employed proteomic and ubiquitinomic analyses to identify direct targets.

Main Results:

• RNF128 is upregulated in human and mouse MASLD livers.
• Hepatocyte-specific RNF128 knockout ameliorated MASLD, while overexpression worsened it.
• RNF128 directly targets and stabilizes SCD1 via K63-linked ubiquitination, promoting lipid accumulation. Therapeutic inhibition of RNF128 alleviated MASLD in vivo.

Conclusions:

• The RNF128-SCD1 axis is a key mechanism driving MASLD pathogenesis.
• Targeting RNF128 presents a promising therapeutic strategy for treating MASLD.