Abstract
Metabolic plasticity enables colorectal cancer (CRC) cells to adapt to energy stress by dynamically adjusting the relative contributions of oxidative phosphorylation (OXPHOS) and glycolysis, thereby contributing to tumor progression and therapeutic resistance. However, pharmacological strategies capable of disrupting this metabolic flexibility remain limited. Here, we identify aripiprazole, an approved antipsychotic drug with emerging anticancer activity, as a disruptor of metabolic plasticity in CRC. Aripiprazole impaired mitochondrial function, reduced OXPHOS-derived ATP production, and initially triggered compensatory glycolytic activation. However, this adaptive response was not sustained, as aripiprazole suppressed monocarboxylate transporter 4 (MCT4), a key lactate transporter involved in glycolytic adaptation under hypoxic stress. Functional experiments showed that MCT4 overexpression attenuated aripiprazole-induced growth inhibition, whereas MCT4 knockdown sensitized CRC cells to hypoxic stress. Mechanistically, RXRα acted as a negative regulator of MCT4. Aripiprazole disrupted the interaction between GNAQ and RXRα, promoted nuclear accumulation of RXRα, thereby repressing MCT4 expression. This blockade of MCT4-dependent glycolytic compensation, together with mitochondrial dysfunction, resulted in ATP depletion and apoptotic cell death in CRC cells. Collectively, our findings reveal a previously unrecognized GNAQ/RXRα/MCT4 signaling axis that sustains metabolic plasticity in CRC and demonstrate that aripiprazole can pharmacologically disrupt this adaptive program. These results provide mechanistic insight into the anticancer activity of aripiprazole and support targeting metabolic plasticity as a therapeutic strategy for CRC.