Energy-Starved Inflammation in Autism: Failure of Glycolytic Compensation Under IL-10–Driven Metabolic Tolerance

Immune activation and metabolic reprogramming are hallmarks of inflammation, yet their coordination in autism spectrum disorder (ASD) remains poorly understood. Here, we introduce the τ-axis, a transcriptomic systems framework that quantifies immune-driven metabolic demand relative to cellular energy-producing capacity, and apply it to whole-blood cohorts from ASD and acute sepsis. Applying τ reveals that comparable inflammatory signaling can arise from fundamentally distinct metabolic states. In sepsis, escalating immune activation is matched by scalable glycolysis and cytosolic substrate-level phosphorylation, enabling effective energetic compensation. In contrast, an IL-10 dominant ASD endotype exhibits elevated inflammatory signaling without proportional metabolic upregulation, resulting in energy-starved inflammation. This uncoupling is reflected in constrained cytosolic energy compensation ratios despite preserved expression of oxidative pathways. Together, these findings establish τ as a generalizable systems metric of immunometabolic demand-capacity mismatch and recast ASD as a chronic immunometabolic syndrome characterized by tractable energetic deficits.