{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T09:38:38Z","timestamp":1765445918518,"version":"3.46.0"},"reference-count":66,"publisher":"Wiley","issue":"46","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82072801","82173316","82473092"],"award-info":[{"award-number":["82072801","82173316","82473092"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Lysosomal exocytosis, a calcium\u2010dependent secretory process, facilitates extracellular release of cargos that promote cancer progression, though its regulatory pathways and therapeutic strategies are poorly understood. Herein, using combined transcriptomic and proteomic approaches, we identify homeobox A1 (HOXA1) as a functional partner of paired like homeodomain 2 (PITX2) within biomolecular condensates forming via liquid\u2013liquid phase separation. Mechanistically, HOXA1\u2010PITX2 complex facilitates the expression of mucolipin 1\n                    <jats:italic>(MCOLN1<\/jats:italic>\n                    ) and RAS\u2010related protein Rab\u20103A (\n                    <jats:italic>RAB3A<\/jats:italic>\n                    ), which drive lysosomal exocytosis of galectin\u20101 (LGALS1) and insulin like growth factor binding protein 7 (IGFBP7) from senescent gastric cancer cells. This process potentiates AKT activation and epithelial\u2010mesenchymal transition, accelerating tumorigenesis and aggressiveness of gastric cancer. Molecular docking and affinity purification assays reveal nortriptyline (Nor) as a potent phase separation disruptor of HOXA1\u2010PITX2 complex. Preclinical studies demonstrate that Nor administration attenuates lysosomal exocytosis\u2010mediated senescence\u2010associated secretory phenotype (SASP) and reduces aggressive phenotypes in gastric cancer models, underscoring the\n                    <jats:italic>HOXA1<\/jats:italic>\n                    \/\n                    <jats:italic>PITX2<\/jats:italic>\n                    axis as a critical regulator of gastric cancer progression. Clinically, elevated expression of\n                    <jats:italic>HOXA1<\/jats:italic>\n                    ,\n                    <jats:italic>PITX2<\/jats:italic>\n                    ,\n                    <jats:italic>MCOLN1<\/jats:italic>\n                    ,\n                    <jats:italic>RAB3A<\/jats:italic>\n                    ,\n                    <jats:italic>LGALS1<\/jats:italic>\n                    , and\n                    <jats:italic>IGFBP7<\/jats:italic>\n                    constitutes a prognostic signature correlating with poor outcomes of gastric cancer patients. Collectively, these results indicate that Nor impedes gastric cancer progression by suppressing HOXA1\u2010PITX2 phase separation and subsequent lysosomal exocytosis\u2010mediated SASP.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512407","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T09:28:22Z","timestamp":1758792502000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nortriptyline Inhibits Lysosomal Exocytosis\u2010Mediated SASP During Gastric Cancer Progression via Targeting HOXA1\u2010PITX2 Phase Separation"],"prefix":"10.1002","volume":"12","author":[{"given":"Yi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Pathology, Union Hospital, Tongji Medical College Huazhong University of Science and Technology  1277 Jiefang Avenue Wuhan Hubei Province 430022 P. R. 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