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Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non\u2010small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome\u20101 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO\u2010induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti\u2010PD\u2010L1\/TGF\u2010\u03b2 bispecific antibody in inhibiting LLC\u2010derived subcutaneous tumor models. Thus, ALO is first identified as a novel late\u2010stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.<\/jats:p>","DOI":"10.1002\/advs.202308307","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T01:59:56Z","timestamp":1719021596000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome\u2010lysosome Fusion in NSCLC"],"prefix":"10.1002","volume":"11","author":[{"given":"Weina","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine Union Hospital, Tongji Medical College Huazhong University of Science and Technology  Wuhan 430000 China"},{"name":"Department of Laboratory Medicine Wuhan Children's Hospital of Tongji Medical College Huazhong University of Science and Technology  Wuhan 430000 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