Metallothionein-Related Findings in Autism Spectrum Disorder: A Systematic Review and Targeted Quantitative Synthesis of Human Studies.

Metallothioneins (MTs) are cysteine-rich proteins that regulate zinc (Zn) and copper (Cu) homeostasis, bind toxic metals, and contribute to redox control. Disturbed trace-element status, oxidative stress, gastrointestinal disease, and immune alterations have been reported in autism spectrum disorder (ASD), raising the question of whether MT biology is altered in this condition. Systematic searches of PubMed, Embase, Web of Science Core Collection, Scopus, Cochrane CENTRAL, and APA PsycINFO were updated on 5 September 2026. Studies directly measuring circulating MT protein, MT isoform mRNA, or anti-MT immunoglobulin G (IgG) antibodies in individuals with ASD, their first-degree relatives, or both were eligible. The review followed PRISMA 2020. Nine reports met the eligibility criteria, comprising eight primary reports and one secondary analysis. Study-level standardized mean differences, risk ratios, and odds ratios were calculated when sufficient published data were available. No pooled meta-analysis was performed because sufficiently comparable datasets were unavailable; otherwise, findings were synthesized narratively. Serum MT protein did not differ significantly between ASD and controls in one study, whereas one small, selected gastrointestinal cohort reported more participants above a study-defined high-MT threshold. In an uncontrolled Zn supplementation study, serum MT-1A increased together with higher serum Zn and lower Cu, but the absence of a concurrent control group precluded causal attribution. Five primary reports assessed MT gene expression, with higher, lower, null, and internally inconsistent findings across different MT isoforms and blood-derived samples; no reproducible ASD-associated transcriptional pattern was identified. Anti-MT antibody findings were also inconsistent across familial, gastrointestinal, and ASD-control comparisons. Across eight primary human reports, MT-related findings in ASD were inconsistent across cohorts, biological matrices, and clinical contexts. Current evidence does not establish a consistent ASD-associated alteration of the MT system, an ASD-specific anti-MT antibody response, or a validated MT biomarker. It also does not determine whether gastrointestinal phenotype, trace-element status, redox biology, immune-related factors, or other variables explain the observed between-study differences. Larger, independently replicated studies using standardized MT measurements and well-characterized populations are required.