Pulmonary fibrosis is a progressive and fatal lung disease characterized by activation of lung fibroblasts and excessive deposition of collagen matrix. We show here that the concentrations of kindlin-2 and its binding partner PYCR1, a key enzyme for proline synthesis, are significantly increased in the lung tissues of human patients with pulmonary fibrosis. Treatment of human lung fibroblasts with TGF-β1 markedly increased the expression of kindlin-2 and PYCR1, resulting in increased kindlin-2 mitochondrial translocation, formation of the kindlin-2–PYCR1 complex, and proline synthesis. The concentrations of the kindlin-2–PYCR1 complex and proline synthesis were markedly reduced in response to pirfenidone or nintedanib, two clinically approved therapeutic drugs for pulmonary fibrosis. Furthermore, depletion of kindlin-2 alone was sufficient to suppress TGF-β1–induced increases of PYCR1 expression, proline synthesis, and fibroblast activation. Finally, using a bleomycin mouse model of pulmonary fibrosis, we show that ablation of kindlin-2 effectively reduced the concentrations of PYCR1, proline, and collagen matrix and alleviate the progression of pulmonary fibrosis in vivo. Our results suggest that kindlin-2 is a key promoter of lung fibroblast activation, collagen matrix synthesis, and pulmonary fibrosis, underscoring the therapeutic potential of targeting the kindlin-2 signaling pathway for control of this deadly lung disease.

肺纤维化是一种进行性和致命的肺部疾病，其特征在于肺成纤维细胞的活化和胶原基质的过度沉积。我们在此表明​​，在患有肺纤维化的人类患者的肺组织中，kindlin-2 及其结合伙伴 PYCR1（脯氨酸合成的关键酶）的浓度显着增加。用 TGF-β1 处理人肺成纤维细胞显着增加 kindlin-2 和 PYCR1 的表达，导致 kindlin-2 线粒体易位、kindlin-2-PYCR1 复合物的形成和脯氨酸合成增加。对吡非尼酮或尼达尼布这两种临床批准的肺纤维化治疗药物的反应，kindlin-2-PYCR1 复合物和脯氨酸合成的浓度显着降低。此外，单独消耗 kindlin-2 足以抑制 TGF-β1 诱导的 PYCR1 表达增加、脯氨酸合成和成纤维细胞活化。最后，使用博莱霉素肺纤维化小鼠模型，我们表明 Kindlin-2 的消融有效降低了 PYCR1、脯氨酸和胶原基质的浓度，并缓解了肺纤维化的进展体内。我们的研究结果表明，kindlin-2 是肺成纤维细胞活化、胶原基质合成和肺纤维化的关键促进剂，强调了靶向 kindlin-2 信号通路以控制这种致命肺部疾病的治疗潜力。