Downregulation of TIMP1 Promotes Ferroptosis and Suppresses Proliferation and Migration of Gastric Cancer Cells via Modulation of the PI3K/AKT Pathway

INTRODUCTION: Tissue inhibitor of metalloproteinase 1 (TIMP1) is essential for the development and progression of various cancers and represents a valuable prognostic indicator. METHODS: The present study utilized in vitro experimental models and comprehensive bio-informatics analyses to systematically investigate the biological function of TIMP1 in gastric cancer. RESULTS: We found a positive correlation between TIMP1 expression and clinical stage in gastric cancer patients. Silencing of the TIMP1 gene markedly impaired the proliferative, invasive, and migratory capacities of gastric cancer cells. Furthermore, downregulation of TIMP1 could retard gastric cancer progression by suppressing the PI3K/AKT signaling pathway, thereby triggering lipid peroxidation and ferroptosis in gastric cancer cells. DISCUSSION: This study reveals that TIMP1 serves as a key regulator of ferroptosis in gastric cancer cells. Specifically, downregulation of TIMP1 inhibits the PI3K/AKT signalling pathway, reduces the intracellular antioxidant defense capacity (e.g., GPX4 and SLC7A11 expression), and consequently induces ferroptosis, accompanied by the suppression of malignant tumour phenotypes. CONCLUSION: This suggests that TIMP1 could serve as a novel biomarker, offering new perspectives on the molecular mechanisms underlying gastric cancer and its treatment.