A lipid-driven, microbe-independent mechanism of acne via Lrig1+ follicular progenitor cells

Sugihira, T.; Tamai, M.; Takagi, K.; Salcman, B.; Kobayashi, T.; Hobro, A. J.; Nakagawa, S.; Takeuchi, Y.; Ishikawa, E.; Maekawa, M.; Owada, Y.; Inohara, N.; Takahashi, H.; Smith, N. I.; Yamasaki, S.; Fujimoto, M.; Nakamura, Y.

doi:10.1101/2025.08.30.673221

bioRxiv · 10.1101/2025.08.30.673221

A lipid-driven, microbe-independent mechanism of acne via Lrig1+ follicular progenitor cells

Sugihira, T.·Tamai, M.·Takagi, K.·Salcman, B.·Kobayashi, T.·Hobro, A. J.·Nakagawa, S.·Takeuchi, Y.·Ishikawa, E.·Maekawa, M.·Owada, Y.·Inohara, N.·Takahashi, H.·Smith, N. I.·Yamasaki, S.·Fujimoto, M.·Nakamura, Y.

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Abstract

Long-chain saturated fatty acids (lcSFAs) are abundant in the skin, but their pathogenic roles in acne remain unclear. In human sebum profiling, C16:0, the most abundant lcSFA, was the only fatty acid significantly elevated in acne and correlated with inflammatory comedone counts. We then established a mouse model that faithfully recapitulates human acne phenotypes, in which topical C16:0 penetrated the epidermis and induced sebocyte hyperplasia, comedogenesis, and follicular inflammation. Mechanistically, C16:0 activated keratinization and inflammatory pathways and drove sebocyte-lineage differentiation from Lrig1+progenitor cells, which function as cutaneous lipid sensors. These effects persisted in germ-free mice and were unaffected by fatty acid transporter modulation, while MyD88 signaling was partially required for inflammatory cell recruitment. Together, our findings identified C16:0 as a human acne-associated lipid that recapitulates disease hallmarks through a microbe-independent, lipid-driven pathway, highlighting Lrig1+cells as central hubs in remodeling of the pilosebaceous unit.

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Sugihira, T., Tamai, M., Takagi, K., Salcman, B., Kobayashi, T., Hobro, A. J., Nakagawa, S., Takeuchi, Y., Ishikawa, E., Maekawa, M., Owada, Y., Inohara, N., Takahashi, H., Smith, N. I., Yamasaki, S., Fujimoto, M., Nakamura, Y.. 2025-08-31. A lipid-driven, microbe-independent mechanism of acne via Lrig1+ follicular progenitor cells. https://doi.org/10.1101/2025.08.30.673221

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