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

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.