The issue of seasonality in wound healing is well known to clinicians: wounds heal faster in spring and autumn, whereas the process often slows during hot summers and cold winters. Observations of venous leg ulcers demonstrate clear seasonal fluctuations in the frequency and rate of repair [1]. In parallel, there is growing interest in local moderate hypothermia as a potential tool to modulate inflammation and promote healing. Against this background, studies that link specific temperature regimes to skin metabolism and the transition from the inflammatory to the proliferative phase are particularly relevant [2].

This very question formed the basis of a study published in the International Journal of Biological Sciences in 2025: the authors set out to determine how "adequate" low temperature affects skin wound healing and through which molecular pathways this effect is realized [3]. Their hypothesis relied on data showing that upon cooling, the body activates fatty acid metabolism, including long-chain omega-3 fatty acids, which possess anti-inflammatory properties [4]. However, a direct link between skin temperature, long-chain fatty acid synthesis, and wound inflammation dynamics had not been previously demonstrated.

Experimental design: from mouse wounds to 3D skin models

Full-thickness skin wounds on the backs of mice were used as a model. After the skin defects were formed, the animals were kept at standard temperature, and after 24 hours, local contact cooling of the wound area and surrounding skin to 20°C, 10°C, or 6°C was initiated. The exposure was performed every two days for 2 minutes using specialized contact cooling devices.

The healing rate was assessed by the degree of epithelial recovery (re-epithelialization) and dermal cell migration on the fourth postoperative day. In parallel, gene activity in the skin was analyzed (transcriptomic analysis), and single-cell analysis data for intact and damaged skin were utilized.

To verify the mechanisms, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), an inhibitor of the ELOVL4 enzyme (an elongase family enzyme responsible for a critical step in fatty acid synthesis), and the pro-inflammatory protein TNFα were injected into the wound area. Additionally, skin tissue-engineered equivalents (3D models), grown from epidermal and dermal cells, were used, with subsequent transplantation onto the wound surface, to test effects in a system as close as possible to living tissue.

Key results: 20°C optimum and the ELOVL4–DHA/EPA pathway

When the skin was cooled to 20°C, wound healing in mice proceeded significantly faster: on the fourth day, epithelial recovery and dermal cell migration were more pronounced than at standard body temperature, whereas at 10°C and 6°C, no such advantage was observed.

Genetic analysis showed that at 20°C, genes associated with epidermal development and keratinization, as well as the fatty acid elongation pathway, were activated. Against this background, the activity of the ELOVL4 enzyme (elongation of very long chain fatty acids protein 4) sharply increased in epidermal cells within the wound zone. Simultaneously, the content of two long-chain omega-3 fatty acids — DHA and EPA — increased in the wound tissue.

Functional experiments confirmed the causal link. The administration of DHA or EPA accelerated healing, enhanced epithelial recovery, and stimulated angiogenesis (vessel growth). Artificial suppression of ELOVL4 slowed wound closure, whereas supplemental administration of DHA or EPA partially restored it. In all models, a decrease in the level of the pro-inflammatory cytokine TNFα (tumor necrosis factor alpha) in the epidermis was associated with a faster transition from inflammation to recovery. In contrast, its increase was associated with delayed healing.

Thus, it is specifically the regime around 20°C that triggers a "metabolic switch" in the skin via ELOVL4 and long-chain omega-3 fatty acids, allowing for the gentle dampening of excessive inflammation and a faster transition of the wound into the active regeneration phase.

Relationship with Inflammation: TNFα suppression and transition to proliferation

Comparing cells with different ELOVL4 activity showed that where the enzyme is inactive, pathways associated with leukocyte recruitment and inflammation are enhanced. Among all factors studied, the Tnfa gene proved to be the most significant. Laboratory tissue staining confirmed that when the wound was treated with DHA and EPA, TNFα levels in the epidermis decreased, whereas blocking ELOVL4 increased them.

With contact cooling to 20°C, the authors observed a steady decline in inflammatory marker levels over the first 3 days after injury. At lower temperatures (10°C and 6°C), inflammation could, conversely, intensify. This highlights the existence of an "optimal temperature window": at 6–10°C, overall cell activity and membrane permeability decrease, hindering normal metabolism and neutralizing the benefits of cooling.

The addition of exogenous TNFα slowed healing: epithelial recovery worsened, and fewer vessels grew. However, cooling to 20°C partially offset this inhibitory effect. The data show that moderate cold helps the body conclude the inflammatory phase in a timely manner and begin the phase of active cell division.

Modeling on skin equivalents: confirmation in a tissue-engineered context

Three-dimensional skin models reproduced the same pattern. The ELOVL4 enzyme functioned predominantly in the epidermal layer of these models. Treatment with DHA and EPA reduced inflammation, while blocking the enzyme intensified it. When these pre-treated models were transplanted into mouse wounds, the groups treated with omega-3 acids demonstrated faster wound closure and high-quality skin restoration. This confirms that the mechanism works not only at the whole-organism level but also at the level of individual tissue structures.

Practical significance and potential applications

From a practical standpoint, the work provides important clues for dermatology and aesthetic medicine.

First, the data explain the seasonality of wound healing. At moderately cool temperatures, an ancient adaptation mechanism is activated, leading to increased synthesis of omega-3 fatty acids and helping to resolve inflammation faster [5].

Second, the results indicate the benefits of controlled cooling (around 20°C) as an adjunct to wound treatment. Importantly, the exposure began 24 hours after injury — when the natural peak of inflammation had already passed. In clinical practice, this will require precise timing: premature suppression of inflammation could be harmful, while timely acceleration of its conclusion is beneficial.

Third, DHA, EPA, and the ELOVL4 enzyme can be considered targets for new drugs to accelerate healing, especially in chronic wounds or inflammatory skin diseases.

The authors note that the study was conducted on mice, and trials on human skin are needed for clinical implementation. It also remains to be studied how temperature affects other important enzymes and processes in the later stages of healing.

Conclusion

The work by Zhou et al. shows that moderate skin cooling to 20°C can accelerate wound healing by activating omega-3 fatty acid synthesis and suppressing excessive inflammation. This temperature exposure helps the wound transition more quickly to the phase of active recovery and vessel growth.

For skincare practitioners, this study provides scientific justification for the temperature regime in postoperative care and opens the way to developing new treatments for complicated wounds based on fatty acid metabolites.

References

1. Simka M. Seasonal variations in the onset and healing rates of venous leg ulcers. Phlebology 2010; 25(1): 29–34. doi:10.1258/phleb.2009.009015.
2. Eming S.A., Murray P.J., Pearce E.J. Metabolic orchestration of the wound healing response. Cell Metab 2021; 33(9): 1726–1743.
3. Zhou S., Li Z., Li K. et al. Contact cooling-induced ELOVL4 enhances skin wound healing by promoting the inflammation-to-proliferation phase transition. Int J Biol Sci 2025; 21(5): 2067–2082.
4. Calder P.C. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 2006; 83(6 Suppl): 1505S–1519S.
5. Peña O.A., Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol 2024; 25: 599–616.