Kaempferol protects melanocytes from ferroptosis by modulating the NF-κB/PTGS2 signaling axis in vitiligo.

Oxidative stress-induced ferroptosis is increasingly recognized as an important contributor to melanocyte destruction in vitiligo; however, the specific upstream signaling networks linking inflammatory signaling to ferroptosis susceptibility remain incompletely defined. Kaempferol, a natural flavonoid and key bioactive constituent of the traditional herb Vernonia anthelmintica (L.) Willd., possesses antioxidant and anti-inflammatory properties, yet its potential to mitigate melanocyte ferroptosis warrants investigation. We established an RSL3 (Ras-selective lethal 3)-induced ferroptosis model in primary human melanocytes and employed a multi-dimensional approach integrating transcriptomic profiling, network pharmacology, molecular docking, and immunofluorescence analysis. Clinical relevance was validated using lesional skin tissues from vitiligo patients. RSL3 challenge triggered canonical ferroptosis features, including lethal lipid peroxidation, glutathione depletion, and characteristic mitochondrial shrinkage, all of which were significantly attenuated by kaempferol. Mechanistically, unbiased transcriptomic and network analyses identified prostaglandin-endoperoxide synthase 2 (PTGS2) as a convergent node associated with both nuclear factor-κB (NF-κB)-driven inflammatory signaling and ferroptosis stress. We found that kaempferol markedly inhibited p65 nuclear translocation, accompanied by suppression of PTGS2 transcription. Notably, pharmacological inhibition of NF-κB using BAY 11-7082 phenocopied the anti-ferroptosis efficacy of kaempferol, supporting the functional involvement of this signaling axis. Furthermore, clinical analyses revealed aberrant activation of the NF-κB/PTGS2 pathway concomitant with ferroptosis signatures in vitiligo lesions. Our findings identify ferroptosis as a critical mechanism of melanocyte injury and delineate an NF-κB/PTGS2-associated signaling framework linking oxidative stress, inflammatory activation, and ferroptosis damage. By modulating this stress-responsive axis, kaempferol confers robust protection against ferroptosis melanocyte injury, highlighting its potential relevance as a ferroptosis-modulating strategy.