The KHK–Polyol Axis as a Convergent Energetic Bottleneck in Chronic Disease Persistence

BACKGROUND: Despite decades of focus on caloric intake and insulin signaling, the global rates of metabolic and neurodegenerative diseases continue to rise. This suggests a fundamental “missing link” in our understanding of cellular energy metabolism. Although various stressors instigate disease, a model that identifies a convergent mechanism capable of preventing cellular recovery across diverse pathologies is lacking. CLAIM/HYPOTHESIS: In fructose-permissive states, unregulated fructose phosphorylation via ketohexokinase (KHK) functions as a convergent energetic sink that can (i) acutely deplete ATP and inorganic phosphate and (ii) promote the net loss of adenine nucleotides through AMP deaminase–linked purine degradation to uric acid under repeated or high-flux conditions. We propose that this creates an energetic hysteresis in which cells remain stabilized in a Cell Danger Response (CDR) phenotype, characterized by mitochondrial fission and reduced energetic flexibility, unless a recovery threshold is exceeded. THE DESCENT INTO FRAGILITY: This study delineates the physical cascade of energy failure. - ENGINE STALL: KHK-linked ATP/Pi depletion and uric-acid–associated aconitase inhibition bias mitochondrial fission, creating a low-efficiency state resistant to recovery by caloric restriction alone. - LOCAL SPREAD: Energetic stress may couple with CD38-linked inflammatory circuits, accelerating NAD+ depletion and impairing NAD+-dependent repair programs. - SYSTEMIC TRIAGE: Vulnerable hypothalamic nodes may downshift high-cost programs (motivation and reproduction) to prioritize survival-driven foraging physiology. The validity of this model rests on the causal necessity of KHK-mediated flux; it would be effectively falsified if metabolic syndrome or hypothalamic energetic failure persists in KHK-deficient human phenotypes (Essential Fructosuria) under identical metabolic stressors. CONCLUSION: By reframing chronic diseases as a crisis of cellular voltage rather than a surplus of fuel, we provide a unified theory that subsumes existing caloric and hormonal models. The model predicts that targeted modulation of the KHK/CD38 axis may function as a testable circuit-breaking intervention to enable energetic recovery (Table 1).