Substantial progress has been made in the management of pulmonary arterial hypertension (PAH) in the past 25 years, but the disease remains life-limiting. Established therapies for PAH are mostly limited to symptomatic relief by correcting the imbalance of vasoactive factors. The tyrosine kinase inhibitor imatinib, the first predominantly non-vasodilatory drug to be tested in patients with PAH, improved exercise capacity and pulmonary haemodynamics compared with placebo but at the expense of adverse events such as subdural haematoma. Given that administration by inhalation might reduce the risk of systemic adverse effects, inhaled formulations of tyrosine kinase inhibitors are currently in clinical development. Other novel therapeutic approaches for PAH include suppression of activin receptor type IIA signalling with sotatercept, which has shown substantial efficacy in clinical trials and was approved for use in the USA in 2024, but the long-term safety of the drug remains unclear. Future advances in the management of PAH will focus on right ventricular function and involve deep phenotyping and the development of a personalized medicine approach. In this Review, we summarize the mechanisms underlying PAH, provide an overview of available PAH therapies and their limitations, describe the development of newer, predominantly non-vasodilatory drugs that are currently being tested in phase II or III clinical trials, and discuss future directions for PAH research.

在过去的 25 年里，肺动脉高压 （PAH） 的管理取得了实质性进展，但这种疾病仍然限制着生命。PAH 的既定疗法大多限于通过纠正血管活性因子的失衡来缓解症状。酪氨酸激酶抑制剂伊马替尼是第一种在 PAH 患者中测试的主要非血管扩张药物，与安慰剂相比，它改善了运动能力和肺血流动力学，但以硬膜下血肿等不良事件为代价。鉴于吸入给药可能会降低全身不良反应的风险，酪氨酸激酶抑制剂的吸入制剂目前正在临床开发中。PAH 的其他新型治疗方法包括用 sotatercept 抑制激活素受体 IIA 型信号传导，该疗法在临床试验中显示出实质性疗效，并于 2024 年在美国获准使用，但该药物的长期安全性仍不清楚。PAH 管理的未来进展将集中在右心室功能上，并涉及深层表型分析和个性化医学方法的开发。在本综述中，我们总结了 PAH 的潜在机制，概述了可用的 PAH 疗法及其局限性，描述了目前正在 II 期或 III 期临床试验中测试的新型、主要是非血管舒张药物的开发，并讨论了 PAH 研究的未来方向。