Linoleic acid improves rosacea through repairing mitochondrial damage in keratinocytes

Rosacea, as a progressive and chronic inflammatory skin disease, lacks safe and effective treatment options. Our previous study reported metabolic disturbance in rosacea patients, containing abnormal lipid metabolism. Building on this, we characterized significant alterations in fatty acid metabolism among rosacea patients, with a notable increase in linoleic acid (LNA) levels. We further demonstrated that LNA prevents rosacea-like dermatitis in LL37-induced rosacea-like mouse model. Our evidence indicated that LNA hyperactivates PPARγ signaling in the epidermis, a phenomenon observed in both rosacea patients and mouse model. Inhibiting PPARγ rescued the effect of LNA in LL37-induced mice. Additionally, our <i>in vivo</i> and <i>in vitro</i> evidence strongly supported the presence of mitochondrial damage in the keratinocytes of rosacea. LNA stimulated PPARγ to reduce the reactive oxygen species production, increasing the generation of ATP and recovering mitochondrial membrane potential. Finally, through a prospective cohort study utilizing UK Biobank data and linkage disequilibrium score regression (LDSC) regression analysis, we further confirmed LNA levels are negatively related to the risk of rosacea, highlighting LNA as a promising therapeutic strategy for rosacea treatment.