A read-through circular RNA RCRIN inhibits metabolic dysfunction-associated steatotic liver disease

Abstract

Background & Aims

The molecular mechanism underlying metabolic dysfunction-associated steatotic liver disease (MASLD) is elusive and whether non-coding RNAs can serve as biomarkers and therapeutic targets of MASLD is less defined.

Methods

Exon capture RNA sequencing analysis was used to identify read-through circRNAs (rt-circRNAs) in livers from three MASLD patients and three patients without MASLD. Hepatocyte-specific deletion or overexpression of rt-circRNA RCRIN were utilized to study MASLD pathogenesis.

Results

We identified 1126 rt-circRNAs in the liver tissues from MASLD patients. RCRIN was highly expressed in normal livers and was downregulated in MASLD livers. Rcrin deletion in hepatocytes caused lipid accumulation and MASLD development, while Rcrin overexpression suppressed the MASLD progression. Mechanistically, in normal hepatocytes, highly expressed RCRIN bound to RPL8 protein to recruit RNF2 for its degradation, reducing RPL8-contained ribosome numbers and lipid accumulation. In MASLD livers, lowerly expressed RCRIN released RPL8 protein to promote RPL8-contained ribosome numbers and lipid synthesis, leading to higher lipid accumulation and ER stress. We synthesized RCRIN and N-acetylgalactosamine (GalNAc)–Rpl8 siRNA to treat established MASLD in mice, both of which suppressed MASLD pathogenesis.

Conclusions

Our findings provide an in vivo function of rt-circRNA RCRIN, show its inhibitory effects in MASLD pathogenesis, indicating RCRIN and RPL8 may be therapeutic targets and candidate nucleic acid drugs for treating MASLD.

Impact and Implications

Our finds reveal a novel mechanism connecting a read-through circRNA RCRIN, ribosome heterogeneity and MASLD pathogenesis. In normal hepatocytes, RCRIN exerts its role by reducing liver lipid accumulation and ER stress through promotion of RPL8 degradation. In MASLD patients, lower RCRIN releases RPL8 to form RPL8-contained ribosomes to promote lipid accumulation and ER stress. RCRIN overexpression and RPL8 depletion dramatically suppresses MASLD development and progression. Our findings indicate that RCRIN and RPL8 might be potential therapeutic targets for treatment of MASLD patients.