Astragaloside IV in type 2 diabetic vascular complications: from traditional mechanisms to an emerging epitranscriptomic (m6A) perspective

Type 2 diabetes mellitus (T2DM) is a significant health problem of global concern, largely attributable to its catastrophic micro- and macro-vascular complications. Astragaloside IV (AS-IV), a major bioactive saponin extracted from Astragalus membranaceus, has emerged as a multi-target therapeutic candidate due to its anti-inflammatory, antioxidant, anti-fibrotic, and pro-survival properties. Dysregulation of N6-methyladenosine (m6A) RNA methylation, as one of the most prevalent epitranscriptomic modifications, has been proposed as a critical contributor to the pathogenesis of diabetic vascular complications, including chronic inflammation, aberrant cell death, and impaired tissue repair. This review integrates these two research fields and proposes a novel concept that modulation of m6A epitranscriptome represents a central mechanism underlying the vascular protective action of AS-IV. New evidence indicates that AS-IV can directly regulate key elements of the m6A machinery, including the upregulation of the methyltransferase methyltransferase-like 3 (METTL3) to enhance sirtuin 1 (SIRT1) expression in diabetic wounds or suppressing the fat mass and obesity-associated protein (FTO) demethylase to suppress inflammatory signaling in diabetic retinopathy. AS-IV acts as a pharmacological modulator of m6A methylation, linking its conventional biological activities to epitranscriptomic regulation. Elucidation of the AS-IV-m6A axis may provide deeper mechanistic understanding and facilitate the development of epitranscriptome-targeted therapies for diabetic vascular complications.