m5C: Novel Diagnostic and Drug Repurposing Targets for Nonalcoholic Steatohepatitis

Comparative and Functional Genomics Pub Date : 2026-02-25 DOI:10.1155/ijog/4309290

Shuxian Chen, Renquan Duan, Jingyi Qiu, Zhiyu Lei, Wei Chen, Xiumei Li

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Abstract

Background

Epigenetic medication, such as RNA 5-methylcytosine (m5C), is well-recognized as a key regulator in hepatic metabolism and immune responses. However, m5C regulatory mechanisms in NASH pathogenesis have not yet been clearly elucidated.

Methods

By utilizing three bulk profiles of NASH patients acquired from GEO and integrative bioinformatic pipelines, such as Limma framework, consensus clustering, and machine learning, we first identified m5C-related molecular subgroups and hub genes for NASH patients. Besides, diagnostic performance and biological characteristics of m5C-related hub gene were estimated at bulk level. Indeed, the heterogeneity of m5C-related hub gene for NASH patients was deciphered in single-cell transcriptomic profiles at temporal and spatial manners, especially in artificial intelligence (AI)-driven virtual cells. Furthermore, potential therapeutic agents targeting m5C-associated hub genes for the treatment of NASH were enriched by AI-driven drug enrichment framework (DrugReflector) based on NASH bulk profile and then validated by molecular docking. Finally, in vitro studies quantified the expression of m5C-associated hub genes compared to normal control.

Results

m5C can divide NASH patients into two various consensus groups with different molecular and immune patterns. Furthermore, ERCC2 and FOXC2 can be considered two upregulated m5C-associated hub genes involved in NASH pathogenesis, which were mainly distributed at cholangiocyte. BRD-K93672499 can be considered a multitarget therapeutic strategy targeting ERCC2 and FOXC2 for the treatment of NASH.

Conclusion

Our study first deciphered the m5C in predictive and therapeutic potential for NASH patients, which gains more insight into their personalized and precision medicine.

Abstract Image

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m5C：非酒精性脂肪性肝炎的新诊断和药物再利用靶点。

背景：表观遗传药物，如RNA 5-甲基胞嘧啶（m5C），被认为是肝脏代谢和免疫反应的关键调节因子。然而，m5C在NASH发病机制中的调控机制尚未明确阐明。方法：通过利用从GEO和综合生物信息学管道（如Limma框架、共识聚类和机器学习）获得的三份NASH患者的大量档案，我们首次确定了NASH患者的m5c相关分子亚群和中心基因。此外，还对m5c相关枢纽基因的诊断性能和生物学特性进行了整体水平的评估。事实上，NASH患者m5c相关中枢基因的异质性在单细胞转录组谱中被时空方式破译，特别是在人工智能（AI）驱动的虚拟细胞中。此外，通过基于NASH体积谱的ai驱动药物富集框架（DrugReflector）对靶向m5c相关中枢基因治疗NASH的潜在药物进行富集，然后通过分子对接进行验证。最后，与正常对照相比，体外研究量化了m5c相关中枢基因的表达。结果：m5C可以将NASH患者分为两个不同的共识组，具有不同的分子和免疫模式。此外，ERCC2和FOXC2可被认为是参与NASH发病的两个m5c相关中心基因上调，主要分布在胆管细胞。BRD-K93672499可以被认为是一种靶向ERCC2和FOXC2治疗NASH的多靶点治疗策略。结论：我们的研究首次揭示了m5C对NASH患者的预测和治疗潜力，为他们的个性化和精准医疗提供了更多的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Comparative and Functional Genomics 生物-生化与分子生物学

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审稿时长

2 months