Inhba is transcriptionally regulated by Foxa1 through the PI3K/AKT signal pathway in acute lung injury.

Acute lung injury (ALI) is a fulminant respiratory failure syndrome with no targeted therapy. We show that Inhba is sharply upregulated in the damaged lung tissue of mice and in BEAS-2B cells, and its abundance tracks with cytokine storm and reactive oxygen species (ROS). Mechanistically, AKT activation is associated with increased FOXA1 phosphorylation and abundance, which transcriptionally induce INHBA; this upregulation of INHBA is a key upstream driver of enhanced ROS production and cytokine release in experimental ALI. Genetic deletion or pharmacologic blockade of PI3K/AKT simultaneously lowered Foxa1 and Inhba, reduced TNF-α, IL-6, and ROS, and improved histologic injury scores and oxygenation. These findings establish the PI3K/AKT-Foxa1-Inhba axis as a central driver in experimental ALI models and support its potential as a druggable target for future investigation. Further validation in human ALI samples will be required to support clinical translation.