Sexual Dimorphism in Metabolic Dysfunction‐Associated Steatotic Liver Disease: The Emerging Role of Non‐Coding <scp>RNAs</scp>

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits marked sexual dimorphism, with lower prevalence and slower progression in premenopausal women versus men and postmenopausal women. While sex hormones, sex chromosome complement, and metabolic differences are contributors, molecular mediators linking biological sex to divergent MASLD trajectories remain incompletely defined. Evidence implicates non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, as critical regulators of gene expression networks implicated in hepatic lipid metabolism, insulin resistance, inflammation, and fibrogenesis in a sex-dependent manner. This review synthesizes epidemiological, experimental, and mechanistic data demonstrating sex-biased hepatic ncRNA expression and its integration with sex hormone signaling, X-chromosome biology, and epigenetic regulation. We propose a hierarchical mechanistic framework in which sex hormones act as upstream regulators that shape hepatic transcriptional and epigenetic landscapes, while ncRNAs function as context-dependent integrative nodes that propagate these signals across cell types, including hepatocytes, Kupffer cells, and hepatic stellate cells. Through this lens, ncRNAs are positioned as key mediators linking hormonal signaling to downstream pathogenic pathways in MASLD. We highlight evidence for ncRNAs as potential sex-specific biomarkers and therapeutic targets, and discuss challenges facing ncRNA-based interventions. We evaluate the current evidence base, noting the predominance of preclinical studies and limited availability of human datasets. Finally, we discuss emerging technologies, including single-cell, spatial, and integrative multi-omics approaches, poised to refine our understanding of sex-specific regulatory networks in MASLD, and emphasize the need for sex-stratified studies to elucidate ncRNA-mediated mechanisms underlying MASLD sexual dimorphism and enable precision medicine strategies tailored to biological sex.