Heme Oxygenase-1 (HO-1) Induces Resistance to Ferroptosis in Gastric Cancer by Targeting GPX4

Abstract

Gastric cancer, a prevalent gastrointestinal tumor, experiences limited efficacy with conventional surgery and chemotherapy. Hence, the imperative to identify additional therapeutic targets is underscored. Numerous studies have reported heme oxygenase-1 (HO-1) for its antioxidant and protective attributes on organs and tissues. In the present study, the role of HO-1 in stimulating the proliferation of gastric cancer cells was explored. The hypothesis posited that HO-1 facilitates gastric cancer progression by regulating GPX4 and ferroptosis. Analysis through bioassay and immunohistochemistry revealed a significant augmentation in HO-1 expression within gastric cancer tissues. Mechanistically, real-time fluorescence quantitative PCR and protein immunoblotting confirmed that HO-1 modulates the protein expression of GPX4, a pivotal player in ferroptosis regulation. Through the upregulation of mRNA expression for GPX4, HO-1 inhibits ferroptosis, thereby fostering gastric cancer progression. This is achieved by elevating GPX4 protein levels and diminishing intracellular reactive oxygen species in gastric cancer cells. In summary, our results elucidate the protective role of high HO-1 expression against ferroptosis in gastric cancer cells, thereby promoting their malignant progression. The upsurge in HO-1 expression emerges as a potential tumor marker and therapeutic target for gastric cancer, offering a novel avenue for intervention.