5-Methylcytidine RNA Epitranscriptomics in Women's Health and Disease: Mechanisms and Clinical Implications.

Chemical modifications of RNA add a dynamic regulatory layer to gene expression beyond the genome and epigenome. Among these modifications, 5-methylcytidine (m5C) has emerged as a key epitranscriptomic modification that influences RNA stability, translation, localization, and stress responses across diverse biological systems. Recent advances in high-resolution mapping and functional interrogation of m5C have revealed its involvement in development, metabolism, immune regulation, and disease pathogenesis. Notably, many of these processes are highly relevant to women's health, which is shaped by hormone-responsive tissues, reproductive transitions, and pregnancy-associated physiological adaptations. In this review, we provide a comprehensive and integrative overview of m5C RNA modification with a focus on its roles in female biology and disease. We summarize the molecular machinery responsible for m5C deposition, recognition, and regulation, as well as current detection technologies. We further highlight emerging evidence linking m5C dysregulation to early embryonic development, women-specific cancers, gynecologic and reproductive disorders, pregnancy complications, and metabolic and cardiovascular diseases. In addition, we discuss the interplay between m5C and sex hormone signaling, as well as the potential of m5C as a biomarker and therapeutic target. Finally, we identify key knowledge gaps, including the need for tissue-specific, longitudinal, single-cell, and spatial epitranscriptomic studies in women. By integrating epitranscriptomics into women's health research, this review underscores m5C as a previously underappreciated regulatory layer with significant implications for precision medicine and clinical translation.