Mesenchymal Stem Cells Attenuate Diabetic Nephropathy by Suppressing the ERK-Ferroptosis-ROS Axis

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease with limited therapeutic options. Ferroptosis contributes to renal tubular injury in DN. This study investigates whether mesenchymal stem cells (MSCs) ameliorate DN by inhibiting ferroptosis and elucidates the underlying mechanism. In a rat model of type 2 DN, MSCs transplantation improved renal function and histopathology, while reducing mitochondrial dysfunction, iron overload, and ROS-driven ferroptosis. In vitro, MSCs reversed high glucose-induced ferroptosis hallmarks in tubular epithelial cells. Mechanistically, RNA sequencing identified the MAPK/ERK pathway as key. MSCs suppressed the p-ERK/ERK-GPX4/ACSL4 axis, preventing glutathione depletion and lipid peroxidation. Activation of ERK abolished MSCs' protection, whereas ERK inhibition mimicked it. These findings reveal that targeting ERK-mediated ferroptosis in renal tubules offers a novel therapeutic strategy, with MSCs acting through this specific mechanism.