{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:58:52Z","timestamp":1790686732404,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200214"],"award-info":[{"award-number":["82200214"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82200214"],"award-info":[{"award-number":["82200214"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hubei Provincial Natural Science Foundation and Xiangyang-of China","award":["2025AFD796"],"award-info":[{"award-number":["2025AFD796"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Objective: T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematological malignancy with poor overall prognosis. This study systematically evaluates the anti-leukemic therapeutic potential and underlying redox-driven mechanisms of PZ2, a novel organic arsenic compound, in T-ALL. Methods: The cytotoxicity of PZ2 against T-ALL cell lines and normal cells was assessed to determine its therapeutic window. RNA-seq was utilized to map transcriptomic alterations. Intracellular redox homeostasis, mitochondrial membrane potential (MMP), cell cycle, and apoptosis were evaluated using flow cytometry and fluorescence microscopy. Ultrastructural changes and key protein expressions were analyzed via TEM, RT-qPCR, and immunoblotting. In vivo efficacy was validated using a T-ALL cell-line-derived xenograft (CDX) mouse model. Results: PZ2 exhibited superior cytotoxicity and an improved safety profile compared to inorganic arsenic trioxide (ATO). Transcriptomic data indicated strong enrichment in apoptosis and autophagy\u2013lysosome pathways. PZ2 induced profound mitochondrial oxidative stress, leading to ROS accumulation, MMP loss, and subsequent activation of caspase-dependent apoptosis\u2014effects that were completely rescued by ROS scavengers. Furthermore, PZ2 triggered G2\/M phase arrest and activated autophagic flux (upregulated GABARAPL1 and LC3-II, degraded p62). Notably, pharmacological inhibition of autophagy rescued PZ2-induced apoptosis, revealing a pro-death autophagic mechanism. In vivo, PZ2 significantly suppressed tumor growth and prolonged survival without overt systemic toxicity. Conclusions: PZ2 exhibits potent anti-T-ALL activity that may involve a dual mechanism: ROS-dependent mitochondrial apoptosis and pro-death autophagy potentially associated with GABARAPL1. This novel organic arsenical may represent a promising and potentially safer alternative for leukemia therapy, and these findings suggest a potential interplay between oxidative stress and autophagic cell death.<\/jats:p>","DOI":"10.3390\/cancers18193150","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:09:25Z","timestamp":1790683765000},"page":"3150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Novel Organic Arsenical PZ2 Exhibits Potent Anti-T-ALL Activity via ROS-Dependent Apoptosis and GABARAPL1-Induced Autophagic Cell Death"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5981-7658","authenticated-orcid":false,"given":"Xian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Qianjiang Central Hospital, Qianjiang 433100, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Zhuping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Postgraduate Union Training Base of Xiangyang No.1 People\u2019s Hospital, School of Medicine, Wuhan University of Science and Technology, Xiangyang 441000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6878-1059","authenticated-orcid":false,"given":"Yujiao","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Separation Membranes and Membrane Processes, School of Chemistry, Tiangong University, Tianjin 300387, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7611-3114","authenticated-orcid":false,"given":"Dongdong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang 441000, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1038\/s41586-024-07807-0","article-title":"The genomic basis of childhood T-lineage acute lymphoblastic leukaemia","volume":"632","author":"Seffernick","year":"2024","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.3324\/haematol.2020.247031","article-title":"Pediatric acute lymphoblastic leukemia","volume":"105","author":"Inaba","year":"2020","journal-title":"Haematologica"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1200\/JCO.2010.30.1382","article-title":"Modern therapy of acute lymphoblastic leukemia","volume":"29","author":"Bassan","year":"2011","journal-title":"J. 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