Caspase-9 activates β-catenin signaling to promote pulmonary fibrosis

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BACKGROUND: Pulmonary fibrosis (PF) is a progressive interstitial lung disease marked by extracellular matrix accumulation and epithelial damage, with limited therapeutic options. Alveolar epithelial cell apoptosis is a key pathological hallmark of PF, but the upstream regulators driving this process remain unclear. Caspase-9, a central initiator of the intrinsic apoptotic pathway, has been implicated in fibrotic diseases across multiple organs. However, its role in lung fibrosis and its molecular interactions are not fully elucidated. METHODS: Caspase-9 expression was analyzed in human PF lung tissues, bleomycin (BLM)-induced mouse models, and TGF-β1-treated MLE-12 alveolar epithelial cells. Functional studies included pharmacological inhibition, siRNA knockdown, and overexpression of Caspase-9. Fibrosis and apoptosis were assessed using Western blot, qPCR, immunohistochemistry, TUNEL, and electron microscopy. Interaction with β-catenin was examined via co-localization, modulation, and rescue experiments. RESULTS: Caspase-9 and cleaved-Caspase-9 were significantly upregulated in fibrotic lungs and TGF-β1-stimulated epithelial cells. Caspase-9 inhibition reduced collagen deposition, improved lung architecture, and suppressed pro-fibrotic markers in mice. In MLE-12 cells, Caspase-9 knockdown attenuated TGF-β1-induced apoptosis, restored E-cadherin, and downregulated fibrotic genes. Conversely, Caspase-9 overexpression aggravated fibrosis and apoptosis. Mechanistically, Caspase-9 interacted with β-catenin, enhanced its nuclear accumulation, and promoted downstream fibrotic signaling. β-catenin silencing reversed Caspase-9-induced fibrosis, while β-catenin activation nullified the protective effects of Caspase-9 inhibition both in vitro and in vivo. These results identify a functional Caspase-9/β-catenin axis in PF progression. CONCLUSIONS: Caspase-9 drives pulmonary fibrosis by promoting epithelial apoptosis and activating β-catenin signaling. Targeting the Caspase-9/β-catenin axis may offer a promising therapeutic strategy for PF.

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