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Existing explanations, including promyelocytic leukemia protein\u2013retinoic acid receptor alpha (PML\u2013RAR\u03b1) mutations and alterations in individual death pathways, do not fully account for the heterogeneity of resistant phenotypes. This review proposes regulated cell death network (RCDN) remodeling as a testable framework for APL resistance. RCDN remodeling is defined as coordinated changes in network coupling, stress routing, and cellular death thresholds. We hypothesize that resistance emerges from coordinated adaptation across redox, survival signaling, and mitochondrial gating, rather than from defects in any single pathway. This predicts coupled shifts across multiple death modules and non-additive responses to combinatorial perturbations, distinguishing network-level remodeling from pathway-specific resistance. We further define experimental criteria for distinguishing network-level remodeling from pathway-specific resistance and discuss Tanshinone IIA (Tan IIA) as a preclinical multi-node perturbation probe.<\/jats:p>","DOI":"10.3390\/biom16091375","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:12:09Z","timestamp":1789999929000},"page":"1375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rethinking Drug Resistance in Acute Promyelocytic Leukemia: The Regulated Cell Death Network as an Integrative Framework"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-8350-7565","authenticated-orcid":false,"given":"Shiyu","family":"Lin","sequence":"first","affiliation":[{"name":"Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China"},{"name":"Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Neurodegenerative Diseases, Changsha Medical University, Changsha 410219, China"},{"name":"School of Traditional Chinese Medicine, Changsha Medical University, Changsha 410219, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biaohan","family":"Qin","sequence":"additional","affiliation":[{"name":"Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China"},{"name":"Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Neurodegenerative Diseases, Changsha Medical University, Changsha 410219, China"},{"name":"School of Traditional Chinese Medicine, Changsha Medical University, Changsha 410219, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhexi","family":"Ye","sequence":"additional","affiliation":[{"name":"Hunan Key Laboratory of the Research and Development 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhen","sequence":"additional","affiliation":[{"name":"Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China"},{"name":"Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Neurodegenerative Diseases, Changsha Medical University, Changsha 410219, China"},{"name":"School of Public Health, Changsha Medical University, Changsha 410219, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sennan","family":"Yang","sequence":"additional","affiliation":[{"name":"Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha 410219, China"},{"name":"Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Neurodegenerative Diseases, Changsha Medical University, Changsha 410219, 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