The YTHDC1-m6A-MEG3 Regulatory Axis in Radiation-Induced Liver Injury: Deciphering Early-Stage Epitranscriptomic...

Radiation-induced liver injury (RILI) remains one of the most severe complications encountered during radiotherapy for hepatocellular carcinoma (HCC), cholangiocarcinoma, and tumors of the right lower lung. Although clinically significant, the molecular mechanisms that drive RILI are still incompletely understood. In our recent study published in Cell Death and Disease, entitled "The YTHDC1 Reader Protein Recognizes and Regulates the lncRNA MEG3 Following Its METTL3-Mediated m6A Methylation: A Novel Mechanism Early During RILI", we investigated in depth the epitranscriptomic regulation of RILI pathogenesis. Post-irradiation, the disease progresses in a staged manner: an early phase characterized by hepatocyte apoptosis and inflammatory activation, a subsequent stage dominated by fibrotic remodeling, and ultimately leading to liver failure. The absence of reliable early biomarkers severely limits timely diagnosis and therapeutic intervention. Among potential candidates, RNA modifications such as N6-methyladenosine (m6A) have emerged as key modulators of cellular stress responses and early pathogenic mechanisms, holding promise as novel diagnostic or therapeutic targets. As a major regulator of RNA metabolism, m6A influences transcript splicing, stability, and translation through the orchestrated actions of classes of proteins known as writers, erasers, and readers. This regulatory layer not only contributes to fundamental processes including DNA repair and inflammatory signaling but also shapes pathological changes via the modulation of lncRNA-chromatin interactions, highlighting its promise for therapeutic exploitation in cancer and RILI. In our study, we identified the long non-coding RNA MEG3 as a pivotal player in RILI, where it promotes apoptosis, drives inflammatory response, and accelerates fibrosis. We further demonstrated that MEG3 expression is tightly controlled by the METTL3-YTHDC1 axis, and YTHDC1-mediated recognition of m6A-modified MEG3 is essential for the progression of RILI. These insights establish the YTHDC1-MEG3 pathway as a key molecular driver of RILI and provide a framework for the design of targeted therapies to mitigate RILI.