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Nortriptyline Inhibits Lysosomal Exocytosis-Mediated SASP During Gastric Cancer Progression via Targeting HOXA1-PITX2

Yi Zhou1, Chunhui Yang2, Xinyue Li2

  • 1Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province, 430022, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|September 25, 2025
PubMed

Insights

Homeobox A1 (HOXA1) and paired like homeodomain 2 (PITX2) drive gastric cancer progression via lysosomal exocytosis. The drug nortriptyline disrupts this complex, reducing cancer aggressiveness and improving patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Lysosomal exocytosis is a calcium-dependent process that releases cargo promoting cancer progression.
  • Regulatory pathways and therapeutic strategies for lysosomal exocytosis in cancer are not well understood.

Purpose of the Study:

  • Identify key regulators of lysosomal exocytosis in gastric cancer.
  • Investigate the therapeutic potential of targeting these regulators.

Main Methods:

  • Combined transcriptomic and proteomic analyses to identify HOXA1 and PITX2.
  • Molecular docking and affinity purification to assess nortriptyline's effect.
  • Preclinical studies in gastric cancer models.

Main Results:

  • HOXA1 and PITX2 form a complex that drives lysosomal exocytosis of LGALS1 and IGFBP7.
  • This process enhances AKT activation and epithelial-mesenchymal transition, promoting gastric cancer.
  • Nortriptyline disrupts the HOXA1-PITX2 complex, reducing senescence-associated secretory phenotype (SASP) and aggressive phenotypes.
  • Elevated HOXA1, PITX2, MCOLN1, RAB3A, LGALS1, and IGFBP7 correlate with poor gastric cancer prognosis.

Conclusions:

  • The HOXA1/PITX2 axis is a critical regulator of gastric cancer progression through lysosomal exocytosis-mediated SASP.
  • Nortriptyline impedes gastric cancer progression by inhibiting HOXA1-PITX2 phase separation and subsequent lysosomal exocytosis.
  • A prognostic signature of key genes (HOXA1, PITX2, MCOLN1, RAB3A, LGALS1, IGFBP7) predicts poor outcomes in gastric cancer patients.
Keywords:
cancer progressionhomeobox A1lysosomal exocytosispaired like homeodomain 2senescence‐ associated secretory phenotype

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