Non-steroidal mineralocorticoid receptor antagonist finerenone ameliorates Diabetic Nephropathy via suppressing SLC7A11-mediated ferroptosis

Diabetic tubulopathy (DT) has recently been identified as a critical pathological feature of diabetic nephropathy (DN). Ferroptosis has emerged as an important pathological factor in DT, implicated in various metabolic disorders, including DN. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor (MR) antagonist, has demonstrated its ability to mitigate kidney inflammation and fibrosis in DN. However, the exact mechanisms underlying these effects remain unclear. SLC7A11 is known for its role in regulating glutathione (GSH) synthesis, which is closely associated with ferroptosis. To investigate how MR modulates SLC7A11-mediated ferroptosis under diabetic and high glucose (HG) conditions, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG treatment. We assessed COL1, TGF-β, ferroptosis-related markers such as GSH and MDA, and proteins linked to ferroptosis, including FTH1, SLC7A11, and GPX4. Additionally, these molecules and proteins were analyzed in the kidneys of diabetic mice treated with FIN. FIN treatment effectively protected the kidneys by inhibiting SLC7A11-mediated ferroptosis in both HG-exposed HK-2 cells and tubular cells from diabetic mice. In summary, our study confirms that the non-steroidal mineralocorticoid receptor antagonist FIN improves diabetic nephropathy by suppressing SLC7A11-mediated ferroptosis, offering potential therapeutic targets and strategies for kidney disease management while providing insights into the mechanisms of clinical drugs.