AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair

Facultative stem cells including alveolar type 2 (AT2) cells in the lung must toggle between unipotent specialization and multipotent plasticity during injury-repair. The underlying molecular switches and epigenetic changes remain unclear yet dictate regeneration versus pathology. Using multiomics and mouse genetics, we show that AP-1 members FOS, FOSB, and JUNB promote an injury-induced transitional AT2 cell state and associated chromatin landscape. Joint transcriptomic-epigenomic profiling and immunostaining distinguish CLDN4+ AT2 cells as a KRT8high subset with open chromatin highly enriched for AP-1 motifs. JUNB and FOSB accumulate in these cells upon viral injury and, along with constitutive FOS, are required for CLDN4 induction, AT2 cell dispersion, and senescence signaling toward fibroblasts, while impacting region-specific alveolar type 1 (AT1) differentiation. AP-1 activation also occurs in mouse AT2 cells expressing oncogenic Kras and transitional cells of human lung adenocarcinoma. Our work refines AT2 transitional states and reveals a gene regulatory logic shared by tissue repair and tumorigenesis.