Xu Wenya, Xie Tian, Zhang Bingli, Zhao Jie, Zhang Lei, Zheng Yamei, Ding Yipeng
Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570311, P.R. China.
Mol Med Rep. 2025 Oct;32(4). doi: 10.3892/mmr.2025.13627. Epub 2025 Jul 25.
Pulmonary fibrosis (PF) is a chronic, progressive lung disease characterized by impaired gas exchange and respiratory difficulties, which can ultimately lead to respiratory failure and mortality. The present study explored the therapeutic effects and underlying mechanisms of oxymatrine (OMT) in an 8‑week‑old C57BL/6 mouse model of bleomycin‑induced PF. The results demonstrated that OMT alleviated lung tissue damage, inflammation and collagen deposition, while promoting autophagy and restoring mitochondrial function. OMT achieved these effects by upregulating apurinic/apyrimidinic endonuclease‑1 (APE1) and activating the PTEN‑induced kinase 1 (PINK1)/Parkin pathway, both of which are key for mitochondrial autophagy. Furthermore, Lewis lung carcinoma mouse lung cancer cells were transduced with an adeno-associated virus containing small interfering RNA and a negative control, and the silencing efficiency was validated by reverse transcription‑quantitative PCR and western blotting. The results revealed a significant reduction in APE1 expression in the knockdown group compared with that in the negative control knockdown group. Immunohistochemistry and immunofluorescence confirmed that OMT increased the expression of APE1, PINK1 and Parkin while reducing markers of fibrosis, such as α‑smooth muscle actin and collagen type I α 1. However, silencing or inhibiting mitochondrial autophagy with mitochondrial division inhibitor‑1 reversed the beneficial effects of OMT, suggesting a key role for APE1 and the PINK1/Parkin pathway in its mechanism of action. These findings provide insights into the antifibrotic potential of OMT and highlight its potential as a basis for the development of new therapies for PF.
肺纤维化（PF）是一种慢性进行性肺部疾病，其特征为气体交换受损和呼吸困难，最终可导致呼吸衰竭和死亡。本研究在8周龄博来霉素诱导的PF C57BL/6小鼠模型中探讨了氧化苦参碱（OMT）的治疗效果及潜在机制。结果表明，OMT减轻了肺组织损伤、炎症和胶原沉积，同时促进了自噬并恢复了线粒体功能。OMT通过上调脱嘌呤/脱嘧啶内切酶-1（APE1）并激活PTEN诱导激酶1（PINK1）/Parkin通路实现了这些作用，这两者都是线粒体自噬的关键。此外，用携带小干扰RNA的腺相关病毒和阴性对照转导Lewis肺癌小鼠肺癌细胞，并通过逆转录-定量PCR和蛋白质印迹法验证沉默效率。结果显示，与阴性对照敲低组相比，敲低组中APE1表达显著降低。免疫组织化学和免疫荧光证实，OMT增加了APE1、PINK1和Parkin的表达，同时减少了纤维化标志物，如α-平滑肌肌动蛋白和I型胶原α1。然而，用线粒体分裂抑制剂-1沉默或抑制线粒体自噬可逆转OMT的有益作用，表明APE1和PINK1/Parkin通路在其作用机制中起关键作用。这些发现为OMT的抗纤维化潜力提供了见解，并突出了其作为PF新疗法开发基础的潜力。
