Tehran University of Medical Sciences Iranian Journal of Psychiatry 1735-4587 21 1 2026 01 01 129 139 Najmeh Sheikhi Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. Faezeh Hajizadeh Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. Jamal Sarvari Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. Zahra Bazi Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Golestan University of Medical Sciences, Gorgan, Iran. Iliad Moradi Department of Laboratory Sciences, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran. Abdolvahab Moradi Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. 2025 05 17 2025 10 26 Objective: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments, restricted interests, and repetitive behaviors. The etiology of ASD is complex, involving genetic and environmental factors. The HECT (Homologous to the E6-AP Carboxyl Terminus) family protein E6-associated protein (E6-AP), encoded by the UBE3A gene, is an ubiquitin ligase implicated in neurological disorders, including Angelman syndrome (AS) and potentially ASD. Dysregulation of E6-AP, influenced by environmental factors such as human papillomavirus (HPV) E6 protein, may contribute to neurodevelopmental abnormalities. Method: This review synthesizes current literature to explore the potential link between HPV E6 protein and E6-AP dysfunction in the context of ASD. We analyzed 32 peer-reviewed studies, including 12 original research articles, 10 reviews, and 10 meta-analyses, retrieved from PubMed and Google Scholar, focusing on E6-AP’s roles in ubiquitin-mediated signaling pathways, its dysregulation in neurodevelopmental disorders, and the impact of HPV E6 on E6-AP function. Results: E6-AP is critical in regulating signaling pathways associated with tumorigenesis and neurodevelopment. Dysregulation of E6-AP, potentially induced by HPV E6, has been implicated in AS and, to a lesser extent, ASD. As visually demonstrated in Figure 1, these complex relationships between HPV, neurodevelopmental disorders, and E6 protein underscore the need for cross-disciplinary research. Current findings indicate that HPV E6 may disrupt E6-AP’s ubiquitin ligase activity, potentially contributing to neurodevelopmental impairments observed in ASD. Conclusion: The potential link between HPV E6 and E6-AP dysfunction underscores a novel avenue for understanding environmental contributors to ASD. Given the complexity of ASD, further research is essential to elucidate E6-AP’s role and to develop targeted therapeutic strategies. This review highlights the need for studies investigating HPV-related mechanisms in ASD to advance effective interventions and support systems. https://ijps.tums.ac.ir/index.php/ijps/article/view/4231 https://ijps.tums.ac.ir/index.php/ijps/article/download/4231/1319