OTOP3 functions as an oncogenic regulator of ferroptosis-mediated colorectal cancer progression.

Abstract

Background: OTOP3, a proton channel located at 17q25.1, drives colorectal cancer growth by enhancing c-Myc stability and inhibiting ferroptosis through GPX4 regulation. Inhibition of OTOP3 suppresses CRC proliferation via c-Myc destabilization, ROS accumulation, and lipid peroxidation, while modulating metabolic shifts linked to the Warburg effect. These findings position OTOP3 as a novel therapeutic target for CRC by disrupting oncogenic signaling and ferroptosis resistance.

Objective: To investigate OTOP3's role in CRC growth/metastasis and its link to ferroptosis and metabolic reprogramming. To evaluate OTOP3 targeting as a therapeutic strategy.

Methods: Colorectal cancer (CRC) cell lines were transfected with OTOP3 siRNA to suppress gene expression, followed by cell viability assays to assess proliferation changes. Western blotting quantified c-Myc and GPX4 levels, while fluorescent probes measured ROS accumulation and lipid peroxidation. Ferroptosis induction was validated using ferroptosis inhibitors, and glycolytic activity was analyzed via glycolysis-related gene expression and lactate production assays.

Results: OTOP3 inhibition destabilized c-Myc, suppressed proliferation, and induced ferroptosis via GPX4 reduction, ROS accumulation, and lipid peroxidation. Altered glycolysis factors indicated enhanced Warburg effect.

Conclusion: Our study provides compelling evidence that targeting OTOP3 effectively suppresses colorectal cancer proliferation by reducing c-Myc protein stability and inducing ferroptosis. These effects are closely associated with metabolic shifts characteristic of the Warburg effect, emphasizing OTOP3 as a potential therapeutic target in colorectal cancer treatment.