Therapeutic targeting of tricarboxylic acid cycle and oxidative phosphorylation: a critical analysis of metabolic interventions in cancer treatment.

Metabolic reprogramming is a hallmark of cancer cells, characterized by distinct alterations in cellular metabolism that emerge during malignant transformation. Enhanced activities of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in tumor cells support their elevated biosynthetic demands for essential biomolecules, including nucleotides, amino acids, and fatty acids. These cancer-specific metabolic reprogramming not only generates mutant targets that are directly druggable, but also induces targets associated with synthetic lethality effects. In this review, we systematically elucidate the molecular dysregulation mechanism of the TCA cycle and the key enzyme OXPHOS, integrate the preclinical and clinical data of existing dysregulated enzyme inhibitors, and also propose a therapeutic approach using metabolic synthetic lethality as a strategy to overcome the toxicity and acquired resistance of targeted therapies in order to achieve selective potentiation of cancer cells on top of conventional targeted therapies. Furthermore, we critically analyze the structural optimization of key inhibitors, providing medicinal chemistry insights into their design, optimization, and mechanisms of action, which are essential for developing next-generation therapeutics with improved efficacy and selectivity. Through comprehensive analysis of altered tumor metabolism, we aim to provide novel insights and perspectives for drug design and target selection in cancer therapeutics.