Therapeutic potential of 2-hexyl-1-decanol in Cutibacterium acnes-induced skin inflammation via modulation of oxidative and inflammatory pathways.

Acne vulgaris is a multifaceted inflammatory disorder in which Cutibacterium acnes-driven oxidative stress and innate immune activation play central pathogenic roles. Despite the clinical need, mechanistically targeted therapies with favorable safety profiles remain limited. Here, we identify 2-hexyl-1-decanol (HD), a naturally derived alkanol, as a potent modulator of C. acnes-induced redox imbalance and inflammatory signaling. Across RAW 264.7 macrophages, primary human peripheral blood mononuclear cells (PBMCs), and a murine inflammation model, HD markedly suppressed ROS accumulation, IL-1β and TNF-α release, and induction of iNOS and COX-2. Mechanistically, HD triggered rapid Nrf2 nuclear translocation and robust HO-1 upregulation, establishing a strong antioxidant response. This redox reprogramming was tightly coupled to selective inhibition of NF-κB activation, while MAPK pathways remained largely unaffected, revealing an unexpected specificity in HD's mode of action. In vivo, HD significantly reduced ear edema, immune-cell infiltration, and cytokine expression, recapitulating its molecular signatures observed in vitro. Together, these findings define HD as a dual-acting Nrf2 activator and NF-κB suppressor that intercepts key pathogenic events in C. acnes-mediated inflammation, positioning it as a promising mechanistically guided candidate for complementary acne therapy.