Targeting Cancer Cell Energy Metabolism in Colorectal Cancer: Opportunities and Challenges from Drug Repositioning

Highlights: What are the main findings? Multiple repurposed drugs act on metabolic vulnerabilities of colorectal cancer (CRC), revealing untapped therapeutic potential beyond their original indications. These agents target key metabolic and signaling pathways (e.g., AMPK/mTOR, glycolysis) to suppress CRC growth and improve response to standard therapies. What are the implications of the main findings? Repositioning existing drugs provides a time- and cost-efficient route to accelerate therapeutic innovation in CRC. Modulating CRC metabolism through repurposed compounds supports precision medicine paradigms and the rational design of combination therapies. Drug repositioning, also known as drug repurposing, represents a cost-effective and time-efficient approach to accelerate the development of novel therapies for colorectal cancer (CRC), the third most common cancer worldwide, with an estimated two million new cases and nearly one million deaths annually. This review aims to critically evaluate how existing non-oncologic drugs can be repositioned to exploit key metabolic vulnerabilities of CRC cells. Targeting cancer cell metabolism offers a unique therapeutic advantage, as it disrupts the bioenergetic and biosynthetic processes that sustain tumor growth, adaptation, and resistance to therapy. Specifically, we examine the mechanisms through which antidiabetic, cardiovascular, anti-inflammatory, antidepressant, and anthelmintic agents interfere with glycolysis, oxidative phosphorylation (OxPhos), and mitochondrial bioenergetics—metabolic circuits central to CRC progression and recurrence. By integrating recent mechanistic, preclinical, and clinical findings, we highlight how these repurposed drugs converge on major metabolic regulators, including the AMPK/mTOR signaling pathways, and how they can potentiate the efficacy of standard chemotherapies and immunotherapies. Furthermore, we discuss the translational challenges that must be addressed to move these compounds into clinical use. Collectively, this review underscores the therapeutic potential of targeting CRC metabolism through drug repositioning as a promising avenue toward more effective and personalized treatment strategies.