Ketohexokinase-Dependent Fructose Metabolism as a Potential Upstream Amplifier of Mast-Cell Activation – A Hypothesis Linking Endogenous Fructose Production, Tissue Danger Signaling, and Impaired Recovery

Why do mast cells remain unusually responsive between episodes in some people with idiopathic mast-cell activation syndrome (MCAS)? We propose that fructose metabolism in surrounding tissue may help sustain this state. Ketohexokinase (KHK) begins fructose metabolism by spending ATP, a molecule that supplies energy for cellular work. If this initial processing outruns the cell’s capacity to handle the products and replenish ATP, it can disturb energy balance and promote oxidative stress. Fructose may come from the diet or be made within the body through the polyol pathway. We hypothesize that KHK-dependent tissue stress increases extracellular signals that heighten mast-cell responses. Mast-cell mediators could then reinforce tissue stress and delay recovery. This mechanism does not require mast cells themselves to lack ATP. Experimental studies support individual steps, but no study reviewed here establishes the complete connection in MCAS. We prioritize signals from neighboring tissue; direct fructose metabolism within mast cells requires separate validation. Proposed experiments would track fructose metabolism, transfer fluid from source tissue to human mast cells, and interrupt KHK separately in each cell population. In models showing both KHK activity and heightened mast-cell responsiveness, we predict that source-tissue KHK interruption will reduce this amplification and shorten recovery without impairing mast-cell function. Failure despite verified KHK inhibition over a predefined recovery interval would weaken the tested mechanism. Luteolin offers an additional probe because it independently inhibits mast-cell activity and shows experimental KHK inhibition; a response cannot identify which action matters. Clinical relevance requires validation in rigorously characterized MCAS populations.