Activation of ERBB4 Pathway Inhibits Pathological Transdifferentiation of Lung Epithelial Progenitors into CD66c ⁺ Basal Cells in Severe Lung Injury

ABSTRACT Aberrant accumulation of basal cells in the distal lung is a hallmark of impaired epithelial regeneration and is closely associated with fibrotic remodeling; however, their cellular origins and the mechanisms governing their expansion remain unclear. Here, this study establishes human distal lung organoids (DLOs) as a physiologically relevant model to investigate epithelial repair. Single‐cell transcriptomic and functional analyses identify a CD66c ⁺ basal cell subset in DLOs that resembles basal cell states enriched in idiopathic pulmonary fibrosis (IPF) lungs and exhibits inflammatory and profibrotic transcriptional programs. The data further demonstrate that secretory cells, alveolar type 2 (AT2) cells, and resident basal cells can each generate CD66c ⁺ basal cells, indicating substantial epithelial lineage plasticity. Mechanistically, the GSK3 inhibitor CHIR99021 stabilizes secretory and AT2 identities and prevents their conversion into CD66c ⁺ basal cells, accompanied by activation of ERBB4‐MAPK signaling. Moreover, exogenous NRG1 directly restricts this transdifferentiation through ERBB4‐dependent signaling, reinforcing the role of ERBB4 in maintaining epithelial lineage stability. Notably, ERBB4 expression is reduced in IPF tissues, coinciding with expansion of the CD66c ⁺ basal cell population. Together, these findings identify ERBB4 signaling as a critical regulator that constrains pathological epithelial remodeling during severe lung injury.