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However, the impact of lysosome\u2010endoplasmic reticulum (ER) interaction on tumor cell fate remains relatively unexplored. A novel interaction between lysosomes and the ER, mediated by the flavonoid LW\u2010213 through targeting LIMP2 (lysosomal integral membrane protein type 2)to activate a lysosomal repair pathway, is identified in acute myeloid leukemia (AML). This leads to activated RAB7A activity, enhancing lysosomal retrograde transport to the perinuclear region and increasing contact at lysosome\u2010ER membrane contact sites (MCSs). Close proximity of TPC1 to IP3R1 at these sites generates a concentrated calcium microdomain, triggering Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010induced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release, which causes cytoplasmic calcium turbulence and two distinct calcium tides. This excessive calcium efflux depletes ER calcium stores, triggering lethal ER stress\u2010induced apoptosis. Interestingly, altering TPC1 expression levels in HeLa cells affected these calcium dynamics, replicating AML\u2010specific mechanisms when overexpressed. Subsequent studies using BALB\/c xenograft models with wild\u2010type and LIMP2\u2010knockout THP1 cells, along with ICR mice toxicity models, confirmed LW\u2010213\u2032s significant tumor growth inhibition with minimal toxicity. These findings underscore the potential of targeting lysosomal\u2010ER calcium crosstalk as an innovative approach to cancer treatment, highlighting the therapeutic promise of LW\u2010213 in managing tumor cell fate through modulating organellar interactions.\n                  <\/jats:p>","DOI":"10.1002\/advs.202415313","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T11:01:22Z","timestamp":1753441282000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Activation of Lysosomal Retrograde Transport Triggers TPC1\u2010IP3R1 Ca\n                    <sup>2+<\/sup>\n                    Crosstalk at Lysosome\u2010ER MCSs Leading to Lethal Depleting of ER Calcium"],"prefix":"10.1002","volume":"12","author":[{"given":"Meng\u2010yuan","family":"Zhu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Carcinogenesis and Intervention Key Laboratory of Drug Quality Control and Pharmacovigilance Ministry of Education Jiangsu Key Laboratory of Drug Design and Optimization China Pharmaceutical University  24 Tongjiaxiang Nanjing 210009 P. 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