The N6-Methyladenosine RNA Demethylase AlkB Homolog 5 (ALKBH5) in Metabolic Diseases: Molecular Mechanisms and Pharmacological Implications-A Review.

Metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated fatty liver disease (MAFLD), are chronic disorders characterized by dysregulated glucose and lipid homeostasis and represent major contributors to insulin resistance, cardiovascular complications, and liver injury. Despite considerable progress in elucidating their pathogenesis, effective preventive and therapeutic strategies remain limited. N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5 (ALKBH5), a nuclear epitranscriptomic "eraser," broadly regulates post-transcriptional gene expression by modulating RNA splicing, nuclear export, stability, and translation. Dysregulation of ALKBH5 has been implicated in tumorigenesis, immune dysfunction, and stress responses, underscoring its wide-ranging biological significance. Emerging evidence further indicates that ALKBH5 plays a pivotal role in maintaining metabolic homeostasis. However, most existing reviews have focused primarily on its roles in cancer, leaving its functions in metabolic diseases relatively unexplored. In this context, this review summarizes the structural characteristics and molecular mechanisms of ALKBH5 and discusses its emerging roles across a spectrum of metabolic diseases, including MAFLD, metabolic complications such as diabetic retinopathy (DR), diabetes-associated cognitive impairment (DACI), atherosclerosis (AS), and diabetic cardiomyopathy (DCM), as well as metabolism-related inflammatory diseases represented by rheumatoid arthritis (RA). Furthermore, recent pharmacological strategies targeting ALKBH5 are discussed, with attention to the challenges posed by its context-dependent, tissue-specific, and disease stage-specific activities. Overall, ALKBH5 emerges as a key epitranscriptomic regulator in metabolic diseases, and advancing therapeutic strategies that account for molecular context and tissue specificity will be critical for achieving safe and effective clinical interventions.