Advances in mitochondrial-targeted colorectal cancer therapy: Mechanistic insights and clinical translation

Colorectal cancer (CRC) therapy is challenged by drug resistance and limited treatment efficacy. Mounting evidence now positions mitochondrial dysfunction as a central mediator of these challenges, making it a compelling therapeutic target. This review synthesizes findings demonstrating that targeting mitochondrial metabolism, apoptosis, dynamics, mitophagy, and intercellular transfer effectively overcomes chemoresistance and restores treatment sensitivity in CRC models. Key mechanisms include the reversal of the Warburg effect, reactivation of intrinsic apoptosis, and disruption of mitochondrial transfer. Clinically, mitochondrial-derived biomarkers, such as cell-free mtDNA, emerge as promising tools for non-invasive monitoring and prognosis. Furthermore, advancements in targeted delivery systems and supportive interventions such as exercise, are shown to enhance therapeutic efficacy and mitigate toxicity. We conclude that integrating mitochondrial-targeted strategies represents a transformative approach for CRC treatment, with future success hinging on overcoming delivery challenges and validating these strategies in personalized models.