Inhibition of ferroptosis exerts renal protective effects in membranous nephropathy rats via the Nrf2/HO-1 pathway.

The incidence of membranous nephropathy (MN) is gradually increasing; however, safe and effective targeted therapies are still lacking. Ferroptosis may be involved in the disease progression of MN; however, the specific pathways involved remain unknown. This study investigated whether the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway mediates MN progression via ferroptosis. A passive Heymann nephritis rat model was established by tail vein injection of anti-Fx1A. The rats were treated with ferrostatin-1 (Fer-1), the ferroptosis inhibitor, and the Nrf2 inhibitor ML385 for 2 weeks. After treatment, 24-h urine protein samples were collected along with blood and renal tissue samples. Renal tissue pathological damage, lipid peroxidation, iron deposition, ferroptosis-related proteins, and expression of the Nrf2/HO-1 pathway were assessed. The passive Heymann nephritis rat model exhibited massive proteinuria, hypoalbuminemia, and hyperlipidemia. Fer-1 reduced proteinuria, alleviated pathological damage to renal tissues, inhibited lipid peroxidation and iron deposition, suppressed ferroptosis in renal tissues, and restored the expression of Nrf2 and HO-1. Furthermore, when the Nrf2 inhibitor ML385 was combined with Fer-1, the inhibition of Nrf2 exacerbated proteinuria, worsened renal tissue pathological damage, increased lipid peroxidation and iron deposition, and aggravated ferroptosis. These findings demonstrated that ferroptosis inhibition alleviates renal injury in MN by activating the Nrf2/HO-1 pathway, suggesting a potential therapeutic target for this disease.