Involvement of disulfidptosis in the pathophysiology of autism spectrum disorder

Abstract

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder, with oxidative stress recognized as a key pathogenic mechanisms. Oxidative stress disrupts intracellular dynamic- thiol/disulfide homeostasis (DTDH), potentially leading to disulfidptosis, a newly identified cell death mechanism. While studies suggest a link between DTDH and ASD, direct evidence implicating disulfidptosis in ASD pathogenesis remains limited. In this study, Mendelian randomization analysis revealed a significant causal association between disulfidptosis-related sulfhydryl oxidase 1 and 2 and ASD (OR1 = 0.883, OR2 = 0.924, p < 0.05). A positive correlation between protein disulfide-isomerase and cognitive performance (OR = 1.021, p < 0.01) further supported the role of disulfidptosis in ASD. Seven disulfidptosis-related genes (TIMP1, STAT3, VWA1, ADA, IL5, PF4, and TXNDC12) were identified and linked to immune cell alterations. A TF-miRNA-mRNA regulatory network and a predictive model (AUC = 0.759) were constructed and external validation datasets (AUC = 0.811). Immune infiltration analysis demonstrated altered expression of naive B cells and three other types of immune cells in ASD children. Animal experiments further validated the differential expression of key genes, highlighting their relevance to ASD pathogenesis. Animal experiments found that BTBR mice exhibit glucose starvation and NADPH depletion, with the specific indicator Slc7a11 being highly expressed. Silencing Slc7a11 can improve core ASD impairments in BTBR mice.

Conclusion

This study establishes the first mechanistic link between disulfidptosis and ASD, identifies seven key genes and their regulatory network, and develops a predictive model with clinical utility. Animal experiments further confirmed the strong association between disulfidpotosis and ASD phenotypes. These findings offer novel therapeutic targets for modulating oxidative stress in ASD.