Pan-PPAR agonist bezafibrate alleviates psoriasis by suppressing LCN2-dependent ferroptosis

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune dysregulation. Recent studies highlight ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, as a key contributor to psoriatic pathogenesis. Lipocalin-2 (LCN2), an iron-binding protein elevated in psoriasis, may regulate this process. We investigated whether bezafibrate (BEZ), a pan-peroxisome proliferator-activated receptor (PPAR) agonist with broad metabolic and anti-inflammatory properties, could ameliorate psoriasis by targeting ferroptosis through LCN2-mediated mechanisms. Our results demonstrated significant ferroptosis activation in psoriatic lesions, characterized by reduced glutathione peroxidase (GPX4) expression, increased acyl-CoA synthetase long-chain family member 4 (ACSL4) and arachidonate 12-lipoxygenase (ALOX12) levels, elevated lipid peroxidation products, and glutathione (GSH) depletion. GPX4 knock-in mice exhibited marked improvement in psoriatic features, confirming ferroptosis involvement. BEZ treatment effectively reduced disease severity, epidermal thickening, and keratinocyte proliferation while restoring redox balance. Lipidomic analysis revealed BEZ reversed imiquimod (IMQ)-induced accumulation of pro-ferroptotic lipids including ceramides, PE (36:4; 1O), PE (34:2; 1O), and PE (16:0_18:1; O). Pathway analysis showed BEZ downregulated arachidonic acid metabolism while enhancing protective ether lipid and sphingolipid pathways. Importantly, BEZ significantly suppressed LCN2 expression, and LCN2 overexpression abolished BEZ's protective effects against ferroptosis and inflammation in keratinocytes. These findings demonstrate that BEZ alleviates psoriasis by inhibiting ferroptosis through LCN2 suppression and lipid metabolic reprogramming, highlighting the therapeutic potential of pan-PPAR activation as a multifaceted strategy for inflammatory skin disorders.