PIM1 is serine/threonine protein kinase that is involved in numerous biological processes. Pulmonary fibrosis (PF) is a chronic pathological result of the dysfunctional repair of lung injury without effective therapeutic treatments. In the current study, we investigated whether PIM1 inhibition would improve bleomycin (BLM)-induced pulmonary fibrosis. In a BLM-induced pulmonary fibrosis model, PIM1 was persistently upregulated in fibrotic lung tissues. Furthermore, PIM1 inhibition by the PIM1-specific inhibitor SMI-4a showed protective effects against BLM-induced mortality. Furthermore, SMI-4a suppressed hydroxyproline deposition and reversed epithelial-mesenchymal transition (EMT) formation, which was characterized by E-cadherin and α-SMA expression in vivo. More importantly, the ZEB1/E-cadherin pathway was found to be closely associated with BLM-induced pulmonary fibrosis. After the in vitro treatment of A549 cells, PIM1 regulated E-cadherin expression by dependently modulating the activity of the transcription factor ZEB1. These findings were verified in vivo after SMI-4a administration. Finally, an shPIM1-expressing adeno-associated virus was delivered via intratracheal injection to induce a long-term PIM1 deficiency in the alveolar epithelium. AAV-mediated PIM1 knockdown in the lung tissues alleviated BLM-induced pulmonary fibrosis, as indicated by collagen accumulation reduction, pulmonary histopathological mitigation and EMT reversion. These findings enhance our understanding of the roles of PIM1 in BLM-induced pulmonary fibrosis and suggest PIM1 inhibition as a potential therapeutic strategy in chronic pulmonary injuries.

PIM1 是丝氨酸/苏氨酸蛋白激酶，参与多种生物过程。肺纤维化（PF）是肺损伤修复功能障碍而没有有效治疗的慢性病理结果。在当前的研究中，我们研究了 PIM1 抑制是否会改善博莱霉素 (BLM) 诱导的肺纤维化。在 BLM 诱导的肺纤维化模型中，PIM1 在纤维化肺组织中持续上调。此外，PIM1 特异性抑制剂 SMI-4a 的 PIM1 抑制显示出对 BLM 诱导的死亡率的保护作用。此外，SMI-4a 抑制羟脯氨酸沉积并逆转上皮间质转化 (EMT) 形成，其特征是体内 E-钙粘蛋白和 α-SMA 表达。更重要的是，ZEB1/E-钙粘蛋白通路被发现与BLM诱导的肺纤维化密切相关。 A549细胞体外处理后，PIM1通过依赖性调节转录因子ZEB1的活性来调节E-钙粘蛋白的表达。这些发现在 SMI-4a 给药后在体内得到了验证。最后，通过气管内注射递送表达shPIM1的腺相关病毒，以诱导肺泡上皮细胞中的长期PIM1缺陷。肺组织中 AAV 介导的 PIM1 敲除减轻了 BLM 诱导的肺纤维化，如胶原蛋白积累减少、肺组织病理学缓解和 EMT 逆转所示。这些发现增强了我们对 PIM1 在 BLM 诱导的肺纤维化中的作用的理解，并表明 PIM1 抑制可作为慢性肺损伤的潜在治疗策略。