Xu Yi, Yan Xiaodi, Feng Tianpu, Liu Yun, Li Xiaoming, Yin Xiaoxing
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China; Clinical Research Center, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China.
Department of Pharmacy, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China.
Ecotoxicol Environ Saf. 2025 Sep 15;303:119007. doi: 10.1016/j.ecoenv.2025.119007. Epub 2025 Sep 6.
Pulmonary arterial hypertension (PAH) is a rare but serious disease that poses a significant threat to patients' quality of life and life expectancy. Perfluorooctane sulfonate (PFOS) is a widely used chemical that, due to its toxicity, persistence, and bioaccumulation properties, may increase the risk of developing PAH with prolonged exposure. This study investigated the molecular mechanisms linking PFOS exposure to PAH by integrating network toxicology and molecular docking methods. Data from multiple authoritative databases (CTD, GeneCards, OMIM, TCMIP, and DAVID) were collected, finally identified 18 target genes and 49 target phenotypes central to PFOS-induced PAH. A PFOS-gene-phenotype-PAH network was constructed, revealing significant upstream and downstream relationships. The analysis highlighted TNF-α and IL6 as pivotal molecular initiators, triggering inflammatory cascades that lead to PAH through established qualitative and quantitative adverse outcome pathways (AOPs). The molecular simulations confirmed that PFOS exposure significantly elevates TNF-α and IL6 levels, initiating a series of inflammatory events that culminate in PAH. These findings not only advance the understanding of PFOS as an environmental trigger for PAH but also offer a computational framework for future risk assessments. By integrating diverse datasets and constructing AOPs, this study provides valuable insights into the environmental factors influencing PAH, offering critical implications for policy-making and regulatory strategies to mitigate PFOS-related health risks.
肺动脉高压（PAH）是一种罕见但严重的疾病，对患者的生活质量和预期寿命构成重大威胁。全氟辛烷磺酸（PFOS）是一种广泛使用的化学物质，由于其毒性、持久性和生物累积特性，长期接触可能会增加患PAH的风险。本研究通过整合网络毒理学和分子对接方法，研究了PFOS暴露与PAH之间的分子机制。收集了来自多个权威数据库（CTD、GeneCards、OMIM、TCMIP和DAVID）的数据，最终确定了18个目标基因和49个PFOS诱导PAH的核心目标表型。构建了PFOS-基因-表型-PAH网络，揭示了显著的上下游关系。分析突出了TNF-α和IL6作为关键分子引发剂，通过既定的定性和定量不良结局途径（AOPs）引发炎症级联反应，导致PAH。分子模拟证实，PFOS暴露显著提高TNF-α和IL6水平，引发一系列炎症事件，最终导致PAH。这些发现不仅推进了对PFOS作为PAH环境触发因素的理解，还为未来的风险评估提供了一个计算框架。通过整合不同的数据集并构建AOPs，本研究为影响PAH的环境因素提供了有价值的见解，为减轻与PFOS相关健康风险的政策制定和监管策略提供了关键启示。
