Dihydroartemisinin inhibits galectin-1-induced ferroptosis resistance and peritoneal metastasis of gastric cancer via the Nrf2-HO-1 pathway.

[BACKGROUND] Peritoneal metastasis (PM) is the predominant mode of gastric cancer (GC) dissemination in patients. The underlying mechanisms remain incompletely understood, and therapeutic interventions are highly challenging. The preemptive interventions of GCPM is particularly important.

[PURPOSE] This study investigated the role and mechanism of galectin-1 within the GC microenvironment in promoting PM and evaluated the inhibitory effects of dihydroartemisinin(DHA) on galectin-1-induced PM.

[METHODS] Through immunohistochemical analysis of clinical samples, database mining, and animal model experiments utilizing lentivirus-transfected GC cells, we investigated the promoting effect of galectin-1 on GCPM. Transcriptomic analysis was conducted to identify potential pathways through which galectin-1 facilitates GCPM, with subsequent validation performed using clinical specimen analysis and both in vitro and in vivo experimental approaches. IC50 of DHA on GC cell lines with LGALS1 overexpression was determined via CCK8 assay. The inhibitory effect of DHA on galectin-1-induced GCPM, along with its underlying mechanism, was further confirmed through in vitro experiments and in vivo animal model interventions. Finally, molecular docking assay was employed to investigate the preliminary mechanism underlying the inhibitory effect of DHA on galectin-1.

[RESULTS] Galectin-1 functions as a key regulatory factor in GCPM and has a significant impact on patient outcomes. It promotes ferroptosis resistance in GC cells by activating the PI3K/Akt/Nrf2/HO-1 signaling pathway, thereby facilitating PM. Moreover, DHA has been shown to target this signaling pathway, effectively inhibiting galectin-1-induced ferroptosis resistance and PM.

[CONCLUSION] To our knowledge, this study is the first to elucidate the mechanism by which galectin-1 promotes PM through enhancement of ferroptosis resistance and to explore the potential of DHA as an inhibitor of this process, thus providing novel strategies for preventing GCPM.