Schizandrin A enhances the sensitivity of gastric cancer cells to 5-FU by promoting ferroptosis

The impact of Schizandrin A (Sch A) on 5-fluorouracil (5-Fu) in gastric cancer (GC) cells is not yet understood, despite its known anticancer and multidrug resistance-reversing properties in various tumors. The objective of this study was to investigate the ability of Sch A to reverse resistance and evaluate its mechanisms in GC cells that are resistant to 5-Fu. 5-Fu-sensitive gastric cancer (GC) cells were subjected to treatment with 5-Fu, while 5-Fu-resistant GC cells AGS/5-Fu and SGC7901/5-Fu were successfully developed. In both in vitro and in vivo settings, the impact of Sch A alone or in combination with 5-Fu on tumor cell growth, proliferation, migration, invasion, and ferroptosis-related metabolism was examined by stimulating these cells. A number of additional experiments were conducted in an attempt to elucidate the molecular mechanism of increased ferroptosis. Findings from our research indicate that the utilization of Sch A alongside 5-Fu could potentially be beneficial in combating drug resistance and treating GC in a reverse manner. The coadministration of Sch A was demonstrated to inhibit metastasis and chemotherapy resistance in 5-Fu-resistant GC cells by promoting the initiation of ferroptosis, a type of cell death that relies on iron. This effect was also confirmed in a xenograft nude mouse model. Through a mechanistic approach, the combined administration of Sch A exhibited a synergistic effect on enhancing the expression of the transferrin receptor. Consequently, this led to the accumulation of iron within cells, triggering lipid peroxidation and ultimately causing the death of 5-Fu-resistant GC cells. In conclusion, the findings from this research have presented a new approach to enhancing GC chemosensitivity, suggesting Sch A as an innovative regulator of ferroptosis. Mechanistically, ferroptosis is induced by Sch A coadministration via increasing transferrin receptor expression.