Targeting p16INK4a reverses alveolar epithelial cell dysfunction and induces lung regeneration in emphysema

Ribeiro Baptista, B.; Toigo, M.; Justeau, G.; Abou-atmeh, P.; De Freitas Castro, T.; Zysman, M.; Thiebaut De Menonville, C.; Audureau, E.; Schnyder, K.; Wang, H.; Hu, Y.; Koenigshoff, M.; Lanone, S.; Chabot, F.; Zana-Taieb, E.; Jourdan Le Saux, C.; Lehmann, M.; Derumeaux, G.; Boczkowski, J.; Gote-Schniering, J.; Boyer, L.

doi:10.1101/2025.09.05.674489

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bioRxiv · 10.1101/2025.09.05.674489

Targeting p16INK4a reverses alveolar epithelial cell dysfunction and induces lung regeneration in emphysema

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Abstract

Pulmonary emphysema involves impaired regenerative capacity of alveolar type 2 epithelial cells (AT2), the main progenitor cells in alveoli. However, the mechanisms underlying dysfunctional epithelial repair remain unclear. In a mouse model of elastase-induced emphysema, we observed an accumulation of activated AT2s in the lung, associated with an overexpression of p16INK4a (p16), a cell cycle inhibitor known to influence stem cell fate. Deletion of p16 promoted the transition of AT2 into alveolar type 1 (AT1) cells, resulting in tissue regeneration in both mice and alveolar organoids. Pharmacological targeting of the p16 pathway using senolytic agents recapitulate this regenerative effect, further supporting the role of p16 as a key brake on epithelial plasticity. These findings demonstrate that alveolar epithelial cell dysfunction can be reversed by p16 deletion or by eliminating p16+ cells, thereby reactivating the AT2-to-AT1 transition and promoting endogenous alveolar regeneration. This work identifies the p16 pathway as a promising therapeutic target for restoring damaged alveoli in emphysema.

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Ribeiro Baptista, B., Toigo, M., Justeau, G., Abou-atmeh, P., De Freitas Castro, T., Zysman, M., Thiebaut De Menonville, C., Audureau, E., Schnyder, K., Wang, H., Hu, Y., Koenigshoff, M., Lanone, S., Chabot, F., Zana-Taieb, E., Jourdan Le Saux, C., Lehmann, M., Derumeaux, G., Boczkowski, J., Gote-Schniering, J., Boyer, L.. 2025-09-07. Targeting p16INK4a reverses alveolar epithelial cell dysfunction and induces lung regeneration in emphysema. https://doi.org/10.1101/2025.09.05.674489

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