Heat shock protein 70/toll-like receptor 2 orchestrates melanocyte ferroptosis in the onset of vitiligo.

Recent advances have deepened our understanding of ferroptotic melanocyte death in vitiligo. Heat shock protein 70 (HSP70) has been identified as a key participant in the pathogenesis of vitiligo, but its direct role in the regulation of melanocyte cell death has been less explored. This study aimed to investigate the mechanism through which HSP70 directly regulates melanocyte ferroptosis. We found that HSP70 activates ferroptosis in melanocytes by binding to toll-like receptor 2 and regulating the MAPK pathway. Our findings confirmed that ferroptosis is activated in the skin lesions of patients with vitiligo. In addition, we found that HSP70 significantly induced ferroptosis in melanocytes. By knocking down different receptor genes, we identified toll-like receptor 2 as the primary receptor mediating HSP70-induced ferroptosis activation in melanocytes. Our results further uncovered that this process involved the inhibition of SLC7A11-glutathione peroxidase 4 and FSP1. Subsequent mechanistic studies revealed that HSP70 promotes ferroptosis through the MAPK pathway, particularly engaging the activation of extracellular signal-regulated kinase and p38 pathways. In summary, the HSP70/toll-like receptor 2 axis triggers melanocytes ferroptosis by activating the MAPK, SLC7A11-glutathione peroxidase 4, and FSP1 pathways, contributing to the onset of vitiligo. Therefore, targeting ferroptosis or toll-like receptor 2 may provide a promising therapeutic approach for the management of vitiligo.