American Journal for Young Scientists · ISSN 3068-9015
When the Krebs Cycle Breaks: Dynamical Modeling of Cancer Metabolism
Authors: Sharanya Mahanta, Sanjana Ramesh
Published: October 23, 2025
Category: Biology
Abstract
Cancer is increasingly recognized as a disease of systems-level dysfunction, where metabolic rewiring plays a central role in sustaining tumor growth and survival. Among these metabolic changes, alterations in the Krebs cycle are particularly notable, as mutations and dysregulation of enzymes such as isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) lead to the accumulation of oncometabolites and disruption of redox homeostasis. Such metabolic perturbations connect directly to the hallmarks of cancer, including sustained proliferative signaling, resistance to cell death, and adaptation to a hostile microenvironment. We employ a mathematical modeling framework based on the Brusselator system of nonlinear oscillators to capture the dynamics of the Krebs cycle under both normal and dysregulated conditions. The canonical Brusselator demonstrates stable oscillations between metabolites, serving as an abstraction of healthy metabolic cycling. We then extend the model to incorporate cytosolic calcium, redox balance, mitochondrial potential, and insulin resistance—factors known to interact with and destabilize mitochondrial metabolism in cancer. Simulations reveal that these extensions lead to dampened oscillations, frequency slowing, and coupled abnormalities across regulatory variables, reflecting a loss of metabolic flexibility consistent with tumorigenesis. By linking Krebs cycle dysfunction to emergent hallmarks of cancer, our approach provides a conceptual bridge between biochemical observations and systems-level insights. This work underscores the utility of nonlinear dynamical models for understanding the complexity of cancer metabolism and suggests new directions for identifying metabolic vulnerabilities that may be exploited therapeutically.