PHLDA1 knockdown exacerbates emphysema in COPD by attenuating proliferation of alveolar type II cells via modulating GLI1 nuclear translocation.

The emphysematous phenotype is an important phenotype in chronic obstructive pulmonary disease (COPD), with substantial morbidity and mortality. The mechanisms underpinning the role of alveolar type II (AT2) cells in alveolar repair within this phenotype remain poorly understood. This study aimed to elucidate the role of PHLDA1, a potential stemness regulator in AT2 cells, on emphysema development. Utilizing mice model, we performed a targeted knockdown of PHLDA1 in AT2 cells and subsequently exposed these mice to tobacco smoke to assess the resultant severity of emphysema and related alveolar damage. We manipulated PHLDA1 expression in AT2 cells line or primary mouse AT2 cells to examine its influence on AT2 stemness-related processes- differentiation, proliferation, and wound closure ability. The specific pathway of PHLDA1 mediated in AT2 cells, as well as its interaction with the GLI1 protein, was further investigated. Mice with reduced PHLDA1 expression developed the emphysema independent of smoking exposure. PHLDA1 knockdown in AT2 cells attenuated their proliferation via the Hedgehog pathway, impairing wound closure ability in the emphysematous phenotype. We also discovered a binding relationship between PHLDA1 and GLI1, where PHLDA1 modulates the nuclear translocation of GLI1, thus regulating the Hedgehog pathway and influencing the stemness and proliferation of AT2 cells. Our study suggests that PHLDA1 is a critical factor in the proliferation process of AT2 cells via modulation of GLI1 nuclear translocation. This regulation is essential to the pathogenesis of the emphysematous phenotype in COPD, signifying potential therapeutic targets for intervention.