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Lycosin\u2010I, a linear amphipathic peptide isolated from the venom of Lycosa singorensis<\/jats:italic>, shows significant anticancer potential. Herein, it is found that Lycosin\u2010I, which can self\u2010assemble into a nanosphere structure, has a multimodal mechanism of action involving lipid binding for the selective and effective treatment of leukemia. Mechanistically, Lycosin\u2010I selectively binds to the K562 cell membrane, likely due to its preferential interaction with negatively charged phosphatidylserine, and rapidly triggers membrane lysis, particularly at high concentrations. In addition, Lycosin\u2010I induces apoptosis, cell cycle arrest in the G1 phase and ferroptosis in K562 cells by suppressing the PI3K\u2010AKT\u2010mTOR signaling pathway and activating cell autophagy at low concentrations. Furthermore, intraperitoneal injection of Lycosin\u2010I inhibits tumor growth of K562 cells in a nude mouse xenograft model without causing side effects. Collectively, the multimodal effect of Lycosin\u2010I can provide new insights into the mechanism of ACPs, and Lycosin\u2010I, which is characterized by high potency and specificity, can be a promising lead for the development of anti\u2010leukemia drugs.<\/jats:p>","DOI":"10.1002\/advs.202404937","type":"journal-article","created":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T05:39:46Z","timestamp":1720071586000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A Lipid\u2010Sensitive Spider Peptide Toxin Exhibits Selective Anti\u2010Leukemia Efficacy through Multimodal Mechanisms"],"prefix":"10.1002","volume":"11","author":[{"given":"Peng","family":"Zhang","sequence":"first","affiliation":[{"name":"The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development College of Life Sciences Hunan Normal University Changsha Hunan 410081 China"},{"name":"Peptide and Small Molecule Drug R&D 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