Cholesterol confers resistance to Apatinib-mediated ferroptosis in gastric cancer.

BACKGROUND: Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Apatinib is a third-line treatment for gastric cancer. However, the development of resistance significantly limits its efficacy, and effective and safe strategies to overcome Apatinib resistance remain elusive. RESULTS: We found that Apatinib-resistant gastric cancer cells (MGC803/AR and AGS/AR) exhibited increased cholesterol synthesis and elevated intracellular cholesterol levels, which contributed to Apatinib resistance. Further investigation identified 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) as one of the most upregulated genes in the cholesterol synthesis pathway. Inhibition of HMGCR not only suppressed the proliferation, migration, and invasion of resistant cells but also reduced their resistance to Apatinib. Moreover, Simvastatin, an HMGCR inhibitor, effectively resensitized resistant cells to Apatinib-induced ferroptosis, thereby enhancing the therapeutic efficacy of Apatinib both in vitro and in vivo. CONCLUSIONS: These findings suggest that Simvastatin may serve as a novel and safe strategy to overcome Apatinib resistance in gastric cancer. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-025-01435-5.