Heat Stress Modulates WDR5‐Mediated H3K4me3 Modification to Induce Melanogenesis via Activating CX3CL1/CX3CR1 Axis

Abstract The skin's unique thermosensitivity renders it exceptionally responsive to thermal perturbations, wherein heat stress exposure disrupts cutaneous homeostasis and activates pigmentary pathways. While clinical observations consistently link heat stress to hyperpigmentation disorders, the precise molecular mechanism for heat‐induced melanogenesis‐particularly the epigenetic‐immune crosstalk mediating this process‐constitutes an unmet research challenge. Transcriptomic analysis of melasma reveals a significant positive correlation between CX3CL1 and melanogenesis. Consistently, CX3CL1 significantly enhances melanogenesis in both cultured skin tissues and melanocytes. Mechanistically, CX3CL1 increases melanogenesis through CX3CR1‐dependent activation of JNK signaling pathway. Notably, heat stress triggers recruitment of WDR5, a core subunit of the H3K4me3 methyltransferase, to the CX3CL1 promoter. At this site, WDR5 catalyzes H3K4me3 modification, thereby driving the transcription of CX3CL1. Inhibition of WDR5 expression can reverse the heat stress‐induced upregulation of H3K4me3 enrichment level in the CX3CL1 promoter region, thereby suppressing CX3CL1 expression and subsequently reducing melanogenesis. Further investigation reveals that the recruitment of WDR5 to the CX3CL1 promoter is MYC‐dependent. In conclusions, heat stress promotes melanogenesis by upregulating CX3CL1 through the MYC‐WDR5‐H3K4me3 axis, thereby activating the CX3CL1/CX3CR1‐JNK signaling pathway. This study elucidates the mechanism by which heat stress regulates skin pigmentation and reveals novel targets with therapeutic potential for pigmentary skin disorders.