Wang Yanying, Wang Jianyi, Zhou Ziheng, Gu Yang, Zhu Xiaoxiao, Yi Zhibin, Cao Changchang, He Lei, Du Ying, Guo Hui, Tian Yong, Fan Zusen
Ministry of Education Key Laboratory of Cell Proliferation and Regulation Biology, Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
Key Laboratory of RNA Science and Engineering, Key Laboratory of Epigenetic Regulation and Intervention, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute for Drug Control, Beijing 102206, China.
J Hepatol. 2025 Jun;82(6):1068-1079. doi: 10.1016/j.jhep.2024.11.052. Epub 2024 Dec 10.
BACKGROUND & AIMS: The molecular mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive and whether non-coding RNAs can serve as biomarkers and therapeutic targets in MASLD has not been determined.
Exon capture RNA-sequencing analysis was used to identify read-through circular RNAs (rt-circRNAs) in livers from three patients with MASLD and three controls without MASLD. Hepatocyte-specific deletion or overexpression of rt-circRNA RCRIN were utilized to study MASLD pathogenesis.
We identified 1,126 rt-circRNAs in liver tissues from patients with MASLD. 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 MASLD progression. Mechanistically, in normal hepatocytes, highly expressed RCRIN bound to RPL8 protein to recruit RNF2 for its degradation, reducing RPL8-containing ribosome numbers and lipid accumulation. In MASLD livers, low RCRIN expression led to the release of RPL8 protein, increasing RPL8-containing ribosome numbers and lipid synthesis, and leading to greater lipid accumulation and endoplasmic reticulum stress. We synthesized RCRIN and N-acetylgalactosamine (GalNAc)-Rpl8 small-interfering RNAs, which both suppressed the pathogenesis of established MASLD in mice.
Our findings reveal an in vivo function of the rt-circRNA RCRIN, show its inhibitory effects in MASLD pathogenesis, and indicate that RCRIN and RPL8 may be therapeutic targets for candidate nucleic acid drugs to treat MASLD.
Our finds reveal a novel mechanism connecting a read-through circular RNA RCRIN, ribosome heterogeneity and metabolic dysfunction-associated steatotic liver disease (MASLD) pathogenesis. In normal hepatocytes, RCRIN exerts its role by reducing liver lipid accumulation and endoplasmic reticulum stress through promotion of RPL8 degradation. In patients with MASLD, lower RCRIN levels lead to the release of RPL8 to form RPL8-containing ribosomes, promoting lipid accumulation and endoplasmic reticulum stress. RCRIN overexpression and RPL8 depletion dramatically suppress MASLD development and progression. Our findings indicate that RCRIN and RPL8 might be potential therapeutic targets for the treatment of patients with MASLD.
代谢功能障碍相关脂肪性肝病（MASLD）的分子机制仍不清楚，非编码RNA是否可作为MASLD的生物标志物和治疗靶点也尚未确定。
采用外显子捕获RNA测序分析，在3例MASLD患者和3例无MASLD的对照者的肝脏中鉴定通读环状RNA（rt-circRNA）。利用肝细胞特异性缺失或过表达rt-circRNA RCRIN来研究MASLD的发病机制。
我们在MASLD患者的肝组织中鉴定出1126种rt-circRNA。RCRIN在正常肝脏中高表达，在MASLD肝脏中表达下调。肝细胞中Rcrin缺失导致脂质蓄积和MASLD发展，而Rcrin过表达抑制MASLD进展。机制上，在正常肝细胞中，高表达的RCRIN与RPL8蛋白结合以募集RNF2进行降解，减少含RPL8的核糖体数量和脂质蓄积。在MASLD肝脏中，RCRIN低表达导致RPL8蛋白释放，增加含RPL8的核糖体数量和脂质合成，导致更大程度的脂质蓄积和内质网应激。我们合成了RCRIN和N-乙酰半乳糖胺（GalNAc）-Rpl8小干扰RNA，二者均抑制已建立的MASLD在小鼠中的发病机制。
我们的研究结果揭示了rt-circRNA RCRIN的体内功能，显示了其在MASLD发病机制中的抑制作用，并表明RCRIN和RPL8可能是治疗MASLD的候选核酸药物的治疗靶点。
我们的研究结果揭示了一种将通读环状RNA RCRIN、核糖体异质性与代谢功能障碍相关脂肪性肝病（MASLD）发病机制联系起来的新机制。在正常肝细胞中，RCRIN通过促进RPL8降解减少肝脏脂质蓄积和内质网应激来发挥作用。在MASLD患者中，较低的RCRIN水平导致RPL8释放以形成含RPL8的核糖体，促进脂质蓄积和内质网应激。RCRIN过表达和RPL8缺失显著抑制MASLD的发生和发展。我们的研究结果表明，RCRIN和RPL8可能是治疗MASLD患者的潜在治疗靶点。
