The synergistic antitumor effects of psoralidin and cisplatin in gastric cancer by inducing ACSL4-mediated ferroptosis.

OBJECTIVE: Cisplatin (DDP) is the major chemotherapeutic drug used to treat gastric cancer (GC). However, DDP-associated side effects and resistance chemoresistance have limited its clinical application. Psoralidin (PSO) is the main extract of Psoralea corylifolia and has antitumor effects. The present study is designed to investigate the antitumor functions and mechanisms of PSO and DDP in GC. METHODS: GC cells (HGC-27 and MKN-45 cells) were treated with PSO (2.5 to 120 µM) and/or DDP. A CCK-8 assay, colony formation assay, and EdU staining were used to test cell proliferation. Cell migration and invasion were tested via a transwell assay. An in vivo assay in nude mice was carried out to analyze the influence of PSO and DDP on tumor growth. H&E staining was conducted to test the histopathological changes of organs and tumor tissues. Ferroptosis-associated indicators, including GSH, MDA, Fe(2+) levels, were examined. Western blotting was conducted to determine the profiles of ACSL4, GPX4, AIFM2, and SLC7A11. RESULTS: PSO impeded GC cell proliferation, migration, invasion, and growth in vivo. PSO exhibited no significant toxic effects on organs and mitigated DDP-mediated liver and kidney injuries. The combination of PSO and DDP exhibited enhanced inhibitory functions. PSO and DDP can significantly promote GC cell ferroptosis. Moreover, PSO promoted ACSL4 expression and suppressed GPX4, AIFM2, and SLC7A11. CONCLUSION: The combination of PSO and DDP has synergistic antitumor effects on GC cells by inducing ACSL4-mediated ferroptosis. PSO may serve as a nontoxic adjuvant to enhance DDP's efficacy and reduce side effects in GC.