Yang Huanyu, Zhang Li, Chen Guanming, Wu Qiongxiao, Li Mingyi, Zhang Chengye, Han Mengjia, Xu Qi
School of Public Health, Binzhou Medical University, Yantai 264003, China.
School of Health Management, Binzhou Medical University, Yantai 264003, China.
Toxicol Appl Pharmacol. 2025 Oct;503:117456. doi: 10.1016/j.taap.2025.117456. Epub 2025 Jul 7.
Pulmonary fibrosis is defined by the excessive accumulation of extracellular matrix proteins, with few treatment options currently available. Notably, emerging evidence indicates that vitamin D may provide benefits for fibrotic lesions across various tissues. However, the underlying molecular mechanisms have not yet been fully elucidated. In our study, we observed that glycolysis levels increased during the fibroblast-to-myofibroblast transition (FMT) in both MRC-5 cells and mouse primary lung fibroblasts, however, vitamin D treatment inhibited fibroblasts' activation, proliferation, and glycolysis in vitro. We further identified signal transducer and activator of transcription 3 (STAT3) as a crucial downstream effector of vitamin D, with the expression of phosphorylated STAT3 (p-STAT3) being negatively regulated by vitamin D. In MRC-5 cells and mouse primary lung fibroblasts, ectopic expression of STAT3 enhanced fibroblast activation and blocked the anti-fibrotic effects of vitamin D. Mechanistic studies revealed that vitamin D reduces p-STAT3 levels, which inhibits the expression of hexokinase-II (HK2), a key enzyme in the glycolytic pathway, consequently blocking fibroblast glycolysis and activation. In vivo experiments demonstrated that vitamin D administration significantly mitigated silica-induced fibrogenesis, while a deficiency in vitamin D exacerbated the progression of pulmonary fibrosis. Collectively, our findings suggest that vitamin D alleviates silica-induced pulmonary fibrosis by inhibiting fibroblast glycolysis in a STAT3/HK2-dependent manner, indicating that vitamin D supplementation may serve as a promising antifibrotic agent.
肺纤维化的定义是细胞外基质蛋白过度积累，目前可用的治疗选择很少。值得注意的是，新出现的证据表明维生素D可能对各种组织的纤维化病变有益。然而，其潜在的分子机制尚未完全阐明。在我们的研究中，我们观察到在MRC-5细胞和小鼠原代肺成纤维细胞的成纤维细胞向肌成纤维细胞转变（FMT）过程中糖酵解水平升高，然而，维生素D处理在体外抑制了成纤维细胞的激活、增殖和糖酵解。我们进一步确定信号转导和转录激活因子3（STAT3）是维生素D的关键下游效应因子，维生素D负向调节磷酸化STAT3（p-STAT3）的表达。在MRC-5细胞和小鼠原代肺成纤维细胞中，STAT3的异位表达增强了成纤维细胞的激活并阻断了维生素D的抗纤维化作用。机制研究表明，维生素D降低p-STAT3水平，从而抑制糖酵解途径中的关键酶己糖激酶-II（HK2）的表达，进而阻断成纤维细胞的糖酵解和激活。体内实验表明，给予维生素D可显著减轻二氧化硅诱导的纤维化，而维生素D缺乏则会加剧肺纤维化的进展。总的来说，我们的研究结果表明，维生素D通过以STAT3/HK2依赖的方式抑制成纤维细胞糖酵解来减轻二氧化硅诱导的肺纤维化，这表明补充维生素D可能是一种有前景的抗纤维化药物。
