A Unified Purinergic-Redox-Inflammasome Cascade in Autism Spectrum Disorder: Formalizing the eATP → SAHH → SAH → GSH → NLRP3 → NMDA Sequence as a Falsifiable Mechanistic Hypothesis

Abstract Background: Autism spectrum disorder (ASD) research is fragmented across three non-communicating literatures: mitochondrial bioenergetics, redox biochemistry, and neuroinflammation. Each field identifies a distinct entry point into ASD pathophysiology without asking what precedes it. This structural isolation has produced robust but disconnected findings and a trail of heterogeneous clinical trials whose failure modes have not been mechanistically explained. Objective: We propose a five-link causal chain hypothesis — the Purinergic-Redox-Inflammasome (PRI) cascade — connecting chronic extracellular ATP (eATP) elevation through S-adenosylhomocysteine hydrolase (SAHH) inhibition, S-adenosylhomocysteine (SAH) accumulation, glutathione (GSH) depletion, and constitutive NLRP3 inflammasome activation to NMDA receptor dysfunction and behavioral phenotype in the CDR-active subtype of ASD. Each link has independent empirical support; the complete five-link sequence has never been tested as an integrated causal model in a single cohort. Methods: Systematic cross-field synthesis of 18+ anchor studies (cumulative n > 52,000) spanning GEO transcriptomics (GSE26415, GSE18123), SPARK biobank purinergic metabolomics (n > 50,000), KidsFirst (n = 6,951), and five meta-analyses. Evidence for each link was graded on a three-tier epistemic scale: (1) Demonstrated in human ASD data, (2) Mechanistically demonstrated in non-ASD systems, (3) Model-predicted. Every claim in this paper carries an explicit epistemic grade. Key findings — the five links: (1) Chronic eATP elevation in ASD: documented by SPARK purinergic metabolomics and Naviaux et al. 2024 (n = 258, 14-pathway CDR profile). (2) eATP-derived adenosine inhibits SAHH, driving SAH accumulation: formally documented by Naviaux 2026; SAH/SAM inversion confirmed in independent ASD methylation meta-analysis 2021. (3) SAH collapse of trans-sulfuration depletes GSH biosynthetically: GSH↓ 27% across 87 studies (n = 9,109, SMD = −0.89, p < 0.0001). (4) ROS from GSH depletion drives constitutive NLRP3 activation: directly demonstrated in ASD-derived lymphoblastoid cells (Vallese et al. 2024). (5) Microglial NLRP3 drives GluN2B internalization via IL-1β, producing E/I imbalance and repetitive behavior reversed by MCC950 (Cell Reports 2025). Critical gap: no study has measured all five biomarkers simultaneously in the same cohort. Unique testable prediction: Purinergic neutralization (suramin or apyrase) should produce a temporally ordered normalization cascade: SAH↓ (Days 1–7) → GSH↑ (Days 7–21) → NLRP3↓ (Days 14–30) → behavioral improvement (Weeks 4–12). This temporal ordering cannot be generated by any single-field model and specifically identifies each broken link if the sequence deviates. Conclusion: SAHH is the unmeasured enzymatic bridge between the purinergic and redox literatures in ASD. Measuring SAHH activity in ASD-derived cells with concurrent eATP profiling is the foundational experiment needed to confirm or refute the PRI cascade. We provide explicit falsification criteria for each link and a minimum viable study design (N = 80–100 observational; N = 20 mechanistic intervention). Keywords: autism spectrum disorder, purinergic signaling, Cellular Danger Response, S-adenosylhomocysteine hydrolase, SAH/SAM ratio, trans-sulfuration, glutathione, NLRP3 inflammasome, NMDA receptor, GluN2B, mechanistic hypothesis, CDR-active subtype