Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive fibrotic interstitial lung disease with limited disease-modifying therapies and poor long-term outcomes. Increasing evidence indicates that senescence of alveolar type II epithelial (AT2) cells is not merely a bystander phenomenon but a central driver of epithelial dysfunction, failed alveolar regeneration, and fibrotic remodeling. In this narrative review, we summarize recent mechanistic, single-cell, epigenetic, and translational studies that have reshaped the epithelial-centered model of IPF. We first outline normal AT2 biology and the regenerative AT2-to-AT1 trajectory, and then discuss how telomere dysfunction, endoplasmic reticulum stress, mitochondrial injury, DNA damage signaling, and aberrant mechanotransduction promote AT2 senescence. We further examine how senescence-associated secretory phenotype (SASP), maladaptive transitional epithelial states, and epithelial-stromal crosstalk sustain fibrosis. Finally, we review emerging therapeutic approaches, including senolytics, senomorphics, pathway-directed interventions, and RNA or epigenetic strategies, while emphasizing current limitations in model systems, biomarker development, delivery, safety, and patient stratification. Together, the available evidence supports AT2 senescence as a pathogenic and potentially targetable axis in IPF.
Zhong et al. (Thu,) studied this question.