Pharmacologic inhibition of IRE1α-dependent decay protects alveolar epithelial identity and prevents pulmonary fibrosis in mice.

ABSTRACT: Stress-induced epithelial plasticity is central to lung regeneration, fibrosis, and malignancy, but how cellular stress leads to differentiation is incompletely understood. Here, we found a central role for IRE1α, a conserved mediator of the unfolded protein response (UPR), in stimulating the plasticity of alveolar type 2 (AT2) cells. In single-cell RNA-seq, IRE1α activity was associated with loss of AT2 identity and progression toward a damage-associated transitional state unique to fibrosis. AT2 plasticity required destructive regulated IRE1α-dependent decay (RIDD), which we demonstrated by deploying PAIR2, a kinase modulator that inhibits RIDD while preserving IRE1α's adaptive XBP1 mRNA splicing activity. In vivo, selective inhibition of RIDD with PAIR2 reduced AT2 differentiation into

SUBMITTER: Auyeung VC 

PROVIDER: S-EPMC12520674 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature