Lu Fei, Wang Gaoming, Yang Xiangzhe, Luo Jing, Ma Haitao, Pan Liangbin, Yao Yu, Xie Kai
Department of Medical Center, Soochow University, Suzhou 215000, China.
Department of Thoracic Surgery, Xuzhou Central Hospital, Clinical School, Xuzhou Medical University, Xuzhou 221009, China.
Pharmaceuticals (Basel). 2025 Jun 9;18(6):859. doi: 10.3390/ph18060859.
Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on the pathway as a potential therapeutic target. We utilized Mendelian Randomization and phenome-wide association analyses on genes involved in sphingolipid metabolism to identify potential regulators of idiopathic pulmonary fibrosis (IPF). A bleomycin-induced mouse model was employed to examine the role of the axis in fibrocyte recruitment, using SKI-349 to target and FTY720 to antagonize . Our analyses revealed as a significant genetic driver of IPF. Targeting and S1PR1 led to a marked reduction in fibrocyte accumulation, collagen deposition, and histopathological fibrosis. Additionally, PAXX and RBKS were identified as downstream effectors of . Our protein-protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. Our findings establish the axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support as a promising therapeutic target.
肺纤维化（PF）是一种进行性间质性肺疾病，其特征为慢性炎症和细胞外基质过度沉积，其中纤维细胞在纤维化重塑中起关键作用。本研究旨在确定调节纤维细胞募集和激活的上游分子机制，重点关注 途径作为潜在治疗靶点。我们对参与鞘脂代谢的基因进行孟德尔随机化和全表型关联分析，以确定特发性肺纤维化（IPF）的潜在调节因子。采用博来霉素诱导的小鼠模型，使用SKI-349靶向 并使用FTY720拮抗 ，以研究 轴在纤维细胞募集中的作用。我们的分析显示 是IPF的一个重要遗传驱动因素。靶向 和S1PR1导致纤维细胞积聚、胶原蛋白沉积和组织病理学纤维化显著减少。此外，PAXX和RBKS被确定为 的下游效应器。我们的蛋白质-蛋白质相互作用图谱表明与现有的抗纤维化药物靶点存在潜在的治疗协同作用。我们的研究结果确立了 轴作为纤维细胞介导的肺纤维化的关键调节因子，并支持 作为一个有前景的治疗靶点。
