Type II alveolar epithelial cell-specific CAP1 loss is associated with spontaneous pulmonary fibrosis and altered complement 5 signaling

Abstract Background Cyclase-associated protein 1 (CAP1) is widely expressed in mammalian tissues; however, its physiological role in the lung remains largely unclear. This study aimed to explore the function of CAP1 in alveolar type 2 (AT2) cells and its potential association with pulmonary fibrosis. Methods and results An inducible AT2 cell–specific CAP1 conditional knockout mouse model (CAP1 f/f ; SFTPC-Cre ERT2 ) was generated. Following tamoxifen induction, CAP1-deficient mice exhibited significantly reduced survival compared with littermate controls. A subset of knockout mice developed progressive deterioration characterized by decreased activity and weight loss, accompanied by impaired lung function, including reduced dynamic lung compliance, forced vital capacity, and forced expiratory volume at 0.05 s, while the FEV 0.05 /FVC ratio remained unchanged. Histological analysis demonstrated spontaneous fibrotic remodeling with disruption of alveolar architecture, inflammatory cell infiltration, and increased Ashcroft scores. Transcriptomic analysis of lungs from deteriorated mice revealed enrichment of extracellular matrix–related pathways and increased expression of fibrosis-associated genes, including Col1a1, Col1a2, and Fn1. Notably, early-phase RNA sequencing performed two weeks after CAP1 deletion identified complement and coagulation cascades among the most altered pathways. Complement component 5 (C5) was significantly downregulated, which was further supported by quantitative PCR and immunohistochemistry. Reduced pulmonary C5 expression was more pronounced during the deteriorated phase. RNA sequencing of isolated CAP1-deficient AT2 cells showed decreased C5 expression together with transcriptional signatures suggestive of mitochondrial pathway alterations. CAP1 knockdown in A549 cells reduced mitochondrial membrane potential as assessed by JC-1 staining, suggesting mitochondrial-related alterations associated with CAP1 deficiency. Conclusions These findings indicate that CAP1 deficiency in AT2 cells is associated with spontaneous fibrotic remodeling and altered complement signaling in the lung. The data support a model in which CAP1 loss may perturb AT2 cell homeostasis and local C5 expression, potentially contributing to fibrotic progression. Further studies are required to clarify the causal relationships and underlying mechanisms.