SLC30A8 (ZnT8) at the crossroads of epigenetics and microRNA regulation in type 2 diabetes and nephropathy.

Diabetic nephropathy (DN) is a major kidney disease and linked to type 2 diabetes mellitus (T2DM), and it significantly which increases the global health burden. In the pathogenesis of DN, ZnT8 is essential for zinc transport into insulin granules; it ensures proper insulin crystallization, storage, and secretion while safeguarding β-cells against oxidative stress. it is suggested that the in pathogenesis of DN, the role of the SLC30A8/ZnT8/PDX-1 axis is underexplored along with its mechanism linking β-cell impairment to T2DM progression and renal fibrosis. In this review, we explore the role of microRNA-mediated regulation of SLC30A8/ZnT8 via PDX-1. Under hyperglycaemic and glucolipotoxic conditions, elevated level of miR-375 and miR-765 suppresses PDX-1 (master regulator of β-cell identity) and transcription of SLC30A8, culminating in ZnT8 silencing. PDX-1 directly binds to SLC30A8 enhancers and modulates its expression. Therapeutic targeting of this pathway via miR-375 and miR-765 antagomirs, CRISPR editing, ZnT8 overexpression, or zinc supplementation offers promise for restoring β-cell function and mitigating DN. Large scale clinical trial and epigenetic studies on patient cohorts will help and guide precision interventions.