卵巢癌（OC）是最常见的妇科恶性肿瘤。化疗失败是OC治疗中的主要挑战。靶向自噬是增强化疗药物细胞毒性的有前途的策略。在本研究中，我们发现苦菜酮（CTD）抑制自噬通路，在体外模型中展现了高疗效，用于OC治疗。在机理上，CTD去活化AMPK/mTOR信号通路，抑制早期自噬启动，并通过破坏SNARE复合物（STX17-SNAP29-VAMP8）形成，在晚期阻止mTORC1依赖的自噬体-溶酶体融合，在OC细胞中导致致命的自噬阻滞。此外，CTD通过在体内外阻止CDDP诱导的自噬，增强OC细胞对顺铂（CDDP）的敏感度。总体而言，我们的数据提供了CTD诱导的自噬阻滞的新生机制洞察，并建议一个新的自噬抑制剂，用于OC的有效治疗。版权所有©2023 Elsevier Inc.。

Ovarian cancer (OC) is the most common gynecological malignancy. Chemotherapy failure is a major challenge in OC treatment. Targeting autophagy is a promising strategy to enhance the cytotoxicity of chemotherapeutic agents. In this study, we found that costunolide (CTD) inhibits autophagic flux and exhibits high therapeutic efficacy for OC treatment in an in vitro model. Mechanistically, CTD inactivates AMPK/mTOR signaling to inhibit autophagy initiation at the early stage and blocks mTORC1-dependent autophagosome-lysosome fusion at the late stage during autophagy by disrupting SNARE complex (STX17-SNAP29-VAMP8) formation, resulting in lethal autophagy arrest in OC cells. Furthermore, CTD sensitizes OC cells to cisplatin (CDDP) by blocking CDDP-induced autophagy both in vitro and in vivo. Together, our data provide novel mechanistic insights into CTD-induced autophagy arrest and suggest a new autophagy inhibitor for effective treatment of OC.Copyright © 2023 Elsevier Inc. All rights reserved.