NOX4 regulates gastric cancer cell invasion and proliferation by increasing ferroptosis sensitivity through regulating ROS

Abstract

Objective: We assessed NOX4 expression in gastric cancer (GC), its prognostic significance, and underlying mechanisms, focusing on promoting ferroptosis through increased ROS production.

Methods: We evaluated NOX4 expression in GC tissues via immunohistochemistry and analyzed correlations with clinicopathological characteristics using TCGA and clinical data. Impacts of manipulating NOX4 levels on GC cell invasiveness, proliferation, and sensitivity to ferroptosis inducers were investigated.

Results: Significantly higher NOX4 expression in GC tissues versus normal adjacent tissues correlated with decreased overall survival and increased tumor aggressiveness. NOX4 was an independent predictor of poor prognosis. Functionally, NOX4 manipulation influenced ROS levels, with overexpression enhancing production. Inhibition of NOX4 or application of antioxidants reduced cancer cell invasion and proliferation. Importantly, NOX4-overexpressing cells showed increased sensitivity to ferroptosis inducers, indicating synergistic effects between NOX4 and ferroptosis in suppressing GC progression.

Conclusion: Our findings highlight NOX4's potential as a therapeutic target in GC, where modulation can enhance efficacy of ferroptosis-inducing treatments, offering a promising strategy for combating this malignancy.

Keywords: Ferroptosis inducer; Gastric cancer; NOX4; Oxidative stress; Sensitivity.