Contact Cooling-Induced ELOVL4 Enhances Skin Wound Healing by Promoting the Inflammation-to-Proliferation Phase Transition

Empirical evidence indicates that the rate of wound healing varies through different seasons, where it is higher in spring and fall but lower in summer and winter, suggesting adequate temperatures may promote wound healing via an unknown mechanism. Here we show that adequate temperature facilitates wound healing by inducing the expression of Elongation of Very Long Chain Fatty Acid Elongase 4 (ELOVL4) that curtails the inflammation phase. Using skin injury and skin organoids models, bulk- and single-cell RNA-sequencing and spatial transcriptomics analysis, and <i>in vivo</i> functional perturbations, we first demonstrate that adjusting skin surface temperature to 20°C by contact cooling markedly increases the rate of wound healing via upregulating ELOVL4 in the injured epidermis. We then reveal docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) as the key products of ELOVL4 that independently control wound healing by dampening the expression of pro-inflammatory cytokines such as tumor necrosis factor α (TNFα). This chain of physiological events enhances wound healing via its timely exit of the inflammatory phase and entry into the proliferation phase of tissue repair. Our findings highlight the skin's adaptability to different temperatures and link the evolutionarily conserved mechanism of long-chain fatty acid synthesis to wound repair while demonstrating the potential application of contact cooling therapy in wound healing.