Loss of Alkbh5 enhances AT2 cell differentiation and alveolar repair across diverse injury models via m6A-dependent Areg signaling.

Efficient regeneration of the alveolar epithelium is essential for restoring lung function after injury, yet the mechanisms that govern alveolar type II cell (AT2) behavior remain insufficiently defined. Here, we identify the m⁶A RNA demethylase Alkbh5 as a pivotal regulator of AT2 cell activation and lineage progression. Conditional deletion of Alkbh5 in AT2 cells markedly enhances their proliferation and differentiation across diverse lung injury contexts-including fibrotic (bleomycin), inflammatory (LPS), mechanical (pneumonectomy), and oxidative (BHT) insults. Loss of Alkbh5 increases m⁶A modification on Amphiregulin (Areg) transcripts, stabilizing its mRNA and elevating Areg expression specifically within transitional AT2 populations. The resulting amplification of EGFR signaling drives accelerated AT2-to-AT1 differentiation and epithelial repair. Supplementation of recombinant Areg phenocopies the regenerative effects of Alkbh5 deletion, whereas Areg neutralization abrogates these responses, establishing Areg as a key downstream effector of Alkbh5. Importantly, ALKBH5 ablation or pharmacologic inhibition in human ESC-derived alveolar organoids similarly promote proliferation, differentiation, and AREG upregulation, demonstrating evolutionary conservation of this regulatory axis. Together, our findings reveal an Alkbh5-Areg-EGFR circuit that orchestrates alveolar epithelial regeneration and suggest new therapeutic opportunities for enhancing lung repair following injury.