S1R mediates NRF2 dependent ferroptosis of renal tubular epithelial cells to promote renal fibrosis in diabetic nephropathy

<b>Rationale</b>: Tubulointerstitial fibrosis is a key pathological aspect of diabetic nephropathy (DN) linked to reduced kidney function. Recent research has identified varied functions of the sigma-1 receptor (S1R) in the pathological fibrosis processes of cardiac, pulmonary, and trabecular meshwork tissues. Nonetheless, the specific roles of S1R in renal fibrosis remain inadequately understood. <b>Objective:</b> This study sought to examine the roles of S1R in the pathogenesis of diabetes-induced renal fibrosis, as well as to elucidate the underlying mechanisms involved. <b>Materials and methods:</b> S1R expression was found in DN patients, db/db mice, and HG-treated HK-2 cells. Loss-of-function studies confirmed S1R's role in nuclear factor erythroid 2-related factor 2 (NRF2) pathway-mediated ferroptosis and renal fibrosis. Molecular docking and co-immunoprecipitation (CO-IP) analysis explored the S1R-NRF2 interaction. <b>Results:</b> S1R was primarily found in tubular epithelial cells and was up-regulated in DN patients, db/db mice, and HG-cultured HK-2 cells. S1R inhibition alleviated ferroptosis and fibrosis in HG stimulated HK-2 cells, while knockdown of NRF2 further abolishes these protective effects by S1R inhibition. As for the further mechanism, S1R combined with NRF2 in HK-2 cells, and knockdown of S1R could increase NRF2 nuclear translocation and up-regulate the expression of phosphorylated NRF2 (p-NRF2), and finally ameliorate ferroptosis and ferroptosis-mediated renal tubular fibrosis. Conclusions: In DN, S1R expression in the kidneys is significantly elevated. It increases p-NRF2 expression, which inhibits NRF2 nuclear translocation, promoting ferroptosis in renal tubular epithelial cells and resulting in tubular fibrosis.