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.