Abstract
Parthenolide (PTN), a sesquiterpene lactone derived from the medicinal plant feverfew (Tanacetum parthenium), and its derivatives such as dimethylamino parthenolide (DMAPT) and dimethylaminomicheliolide fumarate (ACT001) exhibit distinguished anti-inflammatory, anticancer, antioxidant, and epigenetic activities, with accumulating evidence demonstrating their therapeutic potential in respiratory diseases. This review systematically summarizes the antitumor, anti-inflammatory, antioxidative, and antifibrotic effects of PTN and its derivatives in relevant animal models, elucidates the underlying pharmacological mechanisms involving STAT3, NF-κB, MAPK/ERK, and PI3K signaling pathways, and highlights recent advances in clinical applications and drug delivery strategies. A comprehensive literature search was conducted in PubMed, Web of Science, and Scopus up to February 2026. Results demonstrate that PTN and its derivatives exert significant therapeutic effects in lung cancer, pulmonary fibrosis, asthma, pneumonia, and acute lung injury. We summarize the clinical translation progress of ACT001, including its safety and pharmacokinetic profiles, discuss emerging delivery systems such as micelles, and review the patent landscape of PTN derivatives. By integrating mechanistic insights with progress in clinical applications and drug delivery, this review provides a foundation for further mechanistic studies and supports the translational development of PTN-based therapies for respiratory disorders.