The miR-145-5p/NRF2/SLC7A11 axis regulates ferroptosis-mediated renal tubular epithelial cell injury in diabetic nephropathy

作者：Wu G, Fang Y, Xu M, Lu Z, Cao Y, Gao Y · 发表于：Journal of diabetes investigation · 年份：2026 · DOI：10.1111/jdi.70397 · 被引用次数：75 · 研究领域：diabetic nephropathy、ferroptosis、microRNA‐145‐5p

PURPOSE: This study aimed to investigate the molecular mechanism by which the miR-145-5p/NRF2/SLC7A11 axis regulates ferroptosis-mediated renal tubular epithelial cell (RTEC) injury in diabetic nephropathy (DN). METHODS: Male C57BL/KsJ-db/db mice were used as a murine DN model and treated with a miR-145-5p antagomir, adeno-associated virus carrying NRF2 short hairpin RNA (NRF2-shRNA), or the ferroptosis inducer (Erastin) or inhibitor (Ferrostatin-1). Renal function was assessed by measuring the urinary albumin-to-creatinine ratio, serum creatinine, and blood urea nitrogen. Renal histopathological injury and fibrosis were evaluated. In vitro, mouse RTECs (TCMK-1) were exposed to high glucose (HG) and transfected with a miR-145-5p antagomir or small interfering RNAs targeting NRF2 or SLC7A11. The interaction between miR-145-5p and NRF2 was validated using a dual-luciferase assay, while the binding of NRF2 to the SLC7A11 promoter was confirmed by chromatin immunoprecipitation. RESULTS: miR-145-5p expression was upregulated in the kidneys of DN mice. Inhibition of miR-145-5p reduced ferroptosis, attenuated renal histological injury and fibrosis, and reversed epithelial-to-mesenchymal transition. These protective effects were partially abolished by Erastin treatment. Similarly, miR-145-5p inhibition suppressed HG-induced ferroptosis in TCMK-1 cells. Mechanistically, miR-145-5p directly targeted NRF2, and NRF2 bound to the promoter region of SLC7A11. Knockdown of either NRF2 or S...