Yiqi Wenyang Jiedu prescription promotes disulfidptosis of gastric cancer by reversing senescent cancer-associated fibroblasts

BACKGROUND Disulfidptosis is a specific form of cell death that occurs in cells with high SLC7A11 expression when glucose supply is insufficient. HAase, a senescence-associated phenotype secreted by senescent cancer-associated fibroblasts (senCAFs), can upregulate GLUT1 in tumor cells, thereby preventing disulfidptosis. Yiqi Wenyang Jiedu prescription (YWJP) is a Chinese herbal formula, and previous studies have shown that it can improve the clinical efficacy in the treatment of gastric cancer. AIM To investigate whether YWJP promotes gastric cancer cell disulfidptosis via HAase/GLUT1 pathway by reversing cancer-associated fibroblasts (CAFs) senescence and reducing HAase. METHODS CAFs were established using transforming growth factor-β1, and senCAFs were induced by H2O2. Senescence proportion was detected via β-galactosidase staining. ELISA and quantitative PCR measured interleukin-6 (IL-6), interleukin-8 (IL-8), hyaluronic acid, HAase, their mRNAs, NADP+/NADPH ratio, and disulfide bond levels. Western blot detected GLUT1 and disulfidptosis-related proteins. Propidium iodide (PI) staining quantified dead cells. RESULTS Based on previous research methods, we successfully established the CAFs and senCAFs models. The results showed that YWJP effectively reduced the proportion of senCAFs and simultaneously decreased the secretion of IL-6, IL-8, and HAase. Under HAase culture conditions, YWJP significantly downregulated the expression of GLUT1 and disulfidptosis-related proteins (CYFIP1, Rac1, ARP2, and ARP3), increased the disulfide bond level and the proportion of PI-positive cells in MKN45 cells, and thereby promoted disulfidptosis in MKN45 cells. CONCLUSION YWJP promotes disulfidptosis in MKN45 cells by reversing the proportion of senCAFs and reducing HAase secretion.