Cysteine dioxygenase 1 (CDO1) is frequently silenced in various cancers, including gastric cancer (GC), due to promoter hypermethylation, yet its functional role and underlying mechanisms remain poorly understood. In this study, we show that low CDO1 expression correlates with poor prognosis in GC patients. Restoration of CDO1 expression in GC cells significantly suppresses cell proliferation both in vitro and in vivo. Mechanistic investigations reveal that CDO1 inhibits proliferation by elevating oxidative stress, thereby activating the integrated stress response (ISR) in GC cells. High-throughput screening of an antioxidant library identifies Engeletin, a flavanonol glycoside, as an agent capable of mitigating oxidative stress and ISR activation, which in turn diminishes the growth-inhibitory effects of CDO1. Furthermore, either genetic disruption or pharmacological inhibition of the ISR enhances proliferation in CDO1-expressing GC cells. These findings elucidate the molecular mechanisms by which CDO1 exerts its cytostatic effects and highlight its role in regulating GC cell proliferation.
