Abstract

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 (TLR2) and regulating the mitogen-activated protein kinase (MAPK) pathway. Our findings confirmed that ferroptosis is activated in the skin lesions of vitiligo patients. Additionally, we found that HSP70 significantly induced ferroptosis in melanocytes. By knocking down different receptor genes, we identified TLR2 as the primary receptor mediating HSP70-induced ferroptosis activation in melanocytes. Our results further uncovered that this process involved the inhibition of SLC7A11-GPX4 and FSP1. Subsequent mechanistic studies revealed that HSP70 promotes ferroptosis via the MAPK pathway, particularly engaging the activation of extracellular signal-regulated kinase (ERK) and p38 pathways. In summary, the HSP70/TLR2 axis triggers melanocytes ferroptosis by activating the MAPK, SLC7A11-GPX4, and FSP1 pathways, contributing to the onset of vitiligo. Therefore, targeting ferroptosis or TLR2 may provide a promising therapeutic approach for the management of vitiligo.