Lipase GehA functions as a positive-feedback amplifier of Cutibacterium acnes-sebum interactions in acne pathogenesis

Acne vulgaris is a chronic inflammatory disorder of the pilosebaceous unit in which Cutibacterium acnes interacts dynamically with the sebum microenvironment. The bacterial factors that sense and remodel this environment remain poorly characterized. Here, we demonstrate that culturing Cutibacterium acnes in an artificial sebum system enhances bacterial growth and augments inflammatory, lipogenic, and hyperkeratinization-related responses in keratinocytes, sebocytes, and a Syrian hamster flank organ model. Integrated transcriptomic and proteomic analyses identified the secreted lipase glycerol ester hydrolase A (GehA) as a lipid-responsive factor that was markedly upregulated under moderate artificial sebum conditions. Functional studies using recombinant GehA and antibody-mediated neutralization further demonstrated that GehA potentiates host inflammatory, lipogenic, and hyperkeratinization-related responses. Mechanistically, pharmacological inhibition of the TLR2-NLRP3 pathway or the peroxisome proliferator-activated receptor-α-glycerol-3-phosphate acyltransferase 3 axis attenuated inflammatory and lipogenic responses, respectively, supporting a role for these pathways in mediating GehA-induced responses. Notably, recombinant GehA alone was insufficient to induce acne-like pathology in vivo, suggesting that GehA functions as a context-dependent amplifier rather than a primary disease initiator. Collectively, these findings uncover a lipid-induced positive-feedback mechanism through which GehA strengthens Cutibacterium acnes-host interactions and highlight GehA and its downstream signaling pathways as potential therapeutic targets warranting further investigation in acne.