Naringenin inhibits Ferroptosis and ameliorates interstitial cystitis with metabolic syndrome by activating the Nrf2/NQO-1 pathway.

Interstitial cystitis/bladder pain syndrome (IC/BPS) and metabolic syndrome (MetS) are complex disorders with overlapping clinical features, and emerging evidence suggests oxidative stress and ferroptosis may underlie their pathogenesis. Here, using an integrative approach combining bioinformatics, immunohistochemistry, and functional studies in cellular and animal models, we identified NFE2 as a key regulator significantly upregulated in IC/BPS patients, particularly those with MetS comorbidity, where it promotes ferroptosis through competitive inhibition of Nrf2-mediated antioxidant responses, leading to reactive oxygen species accumulation and lipid peroxidation. We further demonstrated that the natural flavonoid naringenin (NAG) specifically binds to NFE2, downregulates its expression, and activates the Nrf2/NQO-1 pathway, resulting in improved bladder function, reduced inflammation, and attenuated fibrosis in animal models. These findings establish NFE2-mediated ferroptosis as a novel pathogenic link between IC/BPS and MetS and identify NAG as a promising therapeutic agent capable of simultaneously targeting metabolic and inflammatory components in refractory IC/BPS patients with metabolic dysfunction.