SGK2 Promotes NEDD4L-Mediated ACSL4 Ubiquitination to Inhibit Ferroptosis and Alleviate Diabetic Kidney Disease

Aims: Despite major advances with sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, progressive tubulointerstitial injury remains a major determinant of renal function decline in diabetic kidney disease (DKD), and the molecular regulators of ferroptotic tubular injury remain incompletely defined. Serum/glucocorticoid-regulated kinase 2 (SGK2), predominantly expressed in renal proximal tubular cells, reportedly regulates ferroptosis in prostate cancer; however, its precise role in DKD remains underexplored. Therefore, this study aimed to investigate the role of SGK2 in tubular ferroptosis in DKD. Results: We identified SGK2 as a ferroptosis-related gene through integrated transcriptomic analyses, which was significantly downregulated in renal tubular cells from patients with DKD and diabetic mice. Functional experiments demonstrated that SGK2 overexpression suppressed lipid peroxidation and ferroptosis, thereby alleviating tubular injury, inflammation, and fibrosis. Mechanistically, SGK2 promoted the association of acyl-CoA synthetase long-chain family member 4 (ACSL4) with the E3 ubiquitin ligase neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) and enhanced K48-linked ubiquitination and proteasomal degradation of ACSL4. Innovation: This study identified SGK2 as a novel negative regulator of ferroptosis in patients with DKD. We found that SGK2 suppresses ferroptosis by promoting NEDD4L-mediated ubiquitination and proteasomal degradation of ACSL4, thereby limiting lipid peroxidation and protecting the renal tubules. The SGK2-ACSL4 axis offers new insights into the molecular regulation of tubular ferroptosis. Conclusion: SGK2 suppresses tubular ferroptosis in DKD through NEDD4L-dependent K48-linked ubiquitination and proteasomal degradation of ACSL4. These findings suggest that SGK2 is a potential regulatory target in DKD and provide a basis for further studies on its role in disease progression. Antioxid. Redox Signal. 00, 000–000.