Metformin Mitigates Diabetes-Driven Renal Senescence via Immunomodulation and the FABP4/FOXO1 Axis

Abstract

Background: Diabetic nephropathy (DN) accelerates renal aging through chronic inflammation and metabolic dysregulation; however, the role of metformin in this process remains incompletely understood. This study investigated whether metformin attenuates diabetes-driven renal senescence through the modulation of the fatty acid-binding protein 4 (FABP4)/forkhead box protein O1 (FOXO1) axis and key immunometabolic enzymes. Methods: Thirty-two male Wistar rats were divided into healthy and diabetic groups and treated with either saline or metformin (200 mg/kg) for 10 weeks. Type 2 diabetes was induced by multiple low doses of streptozotocin (30 mg/kg, intraperitoneally) and high-fat diet. Renal function indices, lipid profile, inflammatory cytokines, succinate dehydrogenase (SDH), ATP-citrate lyase (ACLY), and senescence markers were measured, while FABP4 and FOXO1 expression, macrophage infiltration, and kidney histology were assessed using immunoassays and microscopy. Results: Metformin considerably reduced serum creatinine, urea, and blood urea nitrogen; normalized the lipid profile; suppressed interleukin (IL)-6 and tumor necrosis factor-α; and increased IL-10 levels. Additionally, it reversed DN-associated alterations in SDH and ACLY; downregulated FABP4, FOXO1, and P16INK4a; decreased macrophage infiltration; promoted M2 polarization; and improved renal architecture. Conclusions: This study is the first to demonstrate that metformin mitigates diabetic renal senescence by simultaneously targeting the FABP4/FOXO1 axis and immunometabolic enzymes SDH and ACLY. These findings highlight the translational significance of metformin as a prototype for immunometabolic and immunosenescence-directed therapies in DN.