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Lysosomal exocytosis, a calcium-dependent 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-liquid phase separation. Mechanistically, HOXA1-PITX2 complex facilitates the expression of mucolipin 1 (MCOLN1) and RAS-related protein Rab-3A (RAB3A), which drive lysosomal exocytosis of galectin-1 (LGALS1) and insulin like growth factor binding protein 7 (IGFBP7) from senescent gastric cancer cells. This process potentiates AKT activation and epithelial-mesenchymal 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-PITX2 complex. Preclinical studies demonstrate that Nor administration attenuates lysosomal exocytosis-mediated senescence-associated secretory phenotype (SASP) and reduces aggressive phenotypes in gastric cancer models, underscoring the HOXA1/PITX2 axis as a critical regulator of gastric cancer progression. Clinically, elevated expression of HOXA1, PITX2, MCOLN1, RAB3A, LGALS1, and IGFBP7 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-PITX2 phase separation and subsequent lysosomal exocytosis-mediated SASP.

Abstract licence: CC BY