Corisin induces proteostasis stress to drive epithelial injury and pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disease lacking clarity on the mechanisms linking epithelial injury to fibrotic remodeling. Here, we identify the microbiota-derived corisin as a potent, multifaceted driver of epithelial injury and pulmonary fibrosis. Leveraging targeted DNA sequencing of bronchoalveolar lavage fluid, we provide the first sequence-based identification of corisin in IPF patients and show that functional depletion of native corisin from patient bronchoalveolar lavage fluid abolishes its proapoptotic activity in alveolar epithelial cells. Synthetic corisin readily penetrates epithelial cells, localizes to mitochondria, and induces apoptosis, cellular senescence, and epithelial-mesenchymal transition, effects validated by single-cell transcriptomic analysis. High-throughput protein-interaction screening identifies the ubiquitin-proteasome system as the primary target, demonstrating that corisin enhances proteasome activity and disrupts epithelial proteostasis. Intracellular expression of native corisin recapitulates these cellular pathologies at concentrations relevant to human disease, confirming its high intrinsic potency. Most critically, transgenic mice constitutively expressing native corisin develop spontaneous, progressive pulmonary fibrosis and exhibit exacerbated injury and increased mortality following bleomycin challenge. Collectively, our findings establish corisin as a microbiota-derived effector that directly couples the collapse of epithelial proteostasis to multimechanistic cell-fate dysregulation and fibrotic remodeling, thereby defining a potent and causal microbial-epithelial axis in the pathogenesis of IPF.