Mesenchymal Stem Cells Attenuate Diabetic Nephropathy by Suppressing the ERK-ferroptosis-ROS axis

Background Diabetic nephropathy (DN) is a major cause of end-stage renal disease with limited therapeutic options. As ferroptosis is a key mechanism of renal tubular injury in DN, this study investigates whether mesenchymal stem cells (MSCs) transplantation alleviates DN by inhibiting this form of cell death, although its precise mechanisms remain incompletely understood. Methods To investigate the therapeutic efficacy and mechanisms of human umbilical cord-derived MSCs (UMSCs) in diabetic nephropathy, we established a rat model of type 2 DN (T2DN) using a high-fat diet and streptozotocin. Oxidative stress was assessed via measurements of DNA, protein, and lipid oxidation. To elucidate the underlying mechanisms, RNA sequencing (RNA-seq) was performed to investigate the renal protective effects of UMSCs. Results UMSCs treatment significantly improved renal function and alleviated tubular injury in DN rats, concomitant with reduced mitochondrial dysfunction, iron overload, reactive oxygen species (ROS) accumulation, and ferroptosis. In vitro, UMSCs suppressed high glucose-induced mitochondrial dysfunction, oxidative stress and ferroptosis in renal tubular cells. RNA-seq and experimental findings identified the MAPK/ERK pathway as essential for this protection, confirmed by pharmacological activation/inhibition of p-ERK/ERK. Conclusions Targeting the ERK-ferroptosis-ROS axis in renal tubular epithelial cells represents a novel therapeutic strategy for DN. This strategy is supported by our finding that MSCs confer protection specifically by disrupting the p-ERK/ERK-GPX4/ACSL4 axis, thereby preventing glutathione depletion and lipid ROS accumulation.