Low Temperature Enhances Skin Wound Healing by Activating Long-Chain Fatty Acid Synthesis Which Promotes Exit of the Inflammatory Phase

Abstract

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 appropriate low temperatures may promote wound healing via an unknown mechanism. Here we discover such low temperature which facilitates wound healing by stimulating long-chain fatty acid synthesis that curtails inflammation. Using skin injury and skin organoids models, single-cell RNA-sequencing and spatial transcriptomics analysis, and in vivo functional perturbations, we demonstrate that treatment at 20℃ markedly increases the rate of wound healing by upregulating Elongation of Very Long Chain Fatty Acid Elongase 4 (ELOVL4) in the injured epidermis. We identify 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 reconstructive phase of tissue repair. Our findings highlight the skin adaptability to low temperatures and link the evolutionarily conserved mechanism of long-chain fatty acid synthesis to wound repair while demonstrating the potential application of low-temperature therapy in wound healing.