H3K9 lactylation drives FTO-mediated NRF2 suppression to exacerbate bladder epithelial ferroptosis and inflammation in diabetic bladder dysfunction.

Diabetic bladder dysfunction (DBD), a prevalent yet underexplored complication of diabetes, manifests as debilitating lower urinary tract symptoms (LUTS), such as urinary frequency, urgency, incontinence, and voiding difficulties, significantly impairing quality of life and increasing mortality risks. Current therapies predominantly focus on symptom management, vesicoureteral reflux prevention, and renal protection, with bladder epithelial dysfunction emerging as a crucial pathogenic factor. This study reported significant upregulation of fat mass and obesity-associated protein (FTO) alongside global N6-methyladenosine (m6A) hypomodification in bladder epithelial tissues from patients with DBD and experimental models. Cellular models further demonstrated that FTO accelerated DBD progression by exacerbating ferroptosis and inflammatory responses in bladder epithelial cells. Mechanistically, FTO drived insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2)-dependent recognition of m6A-depleted nuclear factor erythroid 2-related factor 2 (NRF2) transcripts, destabilizing NRF2 mRNA and inhibiting protein expression, with NRF2 restoration demonstrating protective effects in DBD models. Additionally, diabetes-induced FTO overexpression was driven by p300-mediated H3K9 lactylation (H3K9la). These findings collectively identified the H3K9la/FTO/NRF2 axis as a central regulator of epithelial injury in DBD, unveiling novel therapeutic targets for this challenging condition.