N6-Methyladenosine (m6A)-Mediated Regulation of Lipid Metabolism: Molecular Mechanisms, Pathological Implications, and Therapeutic Perspectives

Dysregulated lipid metabolism constitutes the fundamental etiology underlying the global burden of obesity and its associated metabolic disorders. N6-methyladenosine (m6A) is the most abundant reversible chemical modification on messenger RNA and influences virtually every aspect of RNA metabolism. Recent studies demonstrate that m6A mediates regulatory networks governing lipid metabolism and contributes to the pathogenesis of multiple metabolic diseases. However, the precise roles of m6A in lipid metabolism and related metabolic disorders remain incompletely understood. This review positions m6A modification as a central epigenetic switch that governs lipid homeostasis. We first summarize the molecular components of the dynamic m6A regulatory machinery and delineate the mechanisms by which it controls key lipid metabolic processes, with an emphasis on adipogenesis, thermogenesis and lipolysis. Building on this, we further discuss how dysregulated m6A acts as a shared upstream driver linking obesity, type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), and insulin resistance through tissue-specific and inter-organ communication mechanisms. We also evaluate the potential of targeting m6A regulators as therapeutic strategies for precision intervention in metabolic diseases. Ultimately, deciphering the complex interplay between m6A modification and lipid homeostasis offers a promising frontier for the development of epitranscriptome-targeted precision medicine against obesity and its associated metabolic disorders.