Deregulated Nrf2-Keap1-BACH1 axis in autism spectrum disorder.

Scientists studied cells from autistic people and found problems with how these cells handle harmful molecules called oxidative stress. The cells had broken protective systems that normally keep them healthy. When researchers treated the cells with a compound called hemin, it helped fix some of these problems and improved how the cell's energy factories (mitochondria) worked. This suggests new ways to help with autism-related cellular problems.

This study investigated cellular pathways related to oxidative stress in autism spectrum disorder using skin cells from autistic individuals. Researchers found disrupted functioning of the Nrf2-Keap1-BACH1 pathway, which normally helps cells manage oxidative stress. ASD cells showed constitutive Nrf2 activation but reduced levels of protective proteins, along with accumulation of BACH1, a protein that blocks protective responses. The cells also failed to respond normally to sulforaphane, a compound that typically activates protective pathways.

Treatment with hemin restored normal protein expression and improved mitochondrial function, suggesting potential therapeutic targets for addressing oxidative stress imbalances in autism.

Identifies dysregulated oxidative stress pathways as potential therapeutic targets in autism. Hemin or similar compounds targeting the Nrf2-BACH1 pathway may help address cellular dysfunction, though clinical translation requires further investigation in larger studies and brain-relevant models.

Sample size not reported, limiting assessment of findings' generalizability. Study used only dermal fibroblasts, which may not represent brain tissue dysfunction. Unclear if findings translate to clinical symptoms or functional improvements in autism.

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments in social communication, restricted interests, and repetitive behaviors. Although its etiology remains incompletely understood, increasing evidence suggests a multifactorial origin involving genetic alterations, immune dysregulation, and environmental exposures. The aim of this study was to investigate the redox-sensitive Nrf2 signaling pathway in primary dermal fibroblasts isolated from ASD patients. Our results revealed constitutive activation of Nrf2, accompanied by reduced expression of its downstream target heme oxygenase-1 (HO1) and marked nuclear accumulation of the transcriptional repressor BACH1 in ASD cells.

Moreover, ASD fibroblasts failed to increase Nrf2 nuclear translocation upon sulforaphane (SFN) stimulation, a response consistent with elevated basal levels of Keap1, a negative regulator that sequesters Nrf2 in the cytoplasm. Notably, treatment with hemin, known to induce nuclear export and degradation of BACH1, successfully restored HO1 gene and protein expression and ameliorated impaired mitochondrial function in ASD fibroblasts, as suggested by the decrease of mtROS levels and the restored mitochondrial membrane potential. Collectively, these results identify a dysregulation of the Nrf2-Keap1-BACH1 axis in ASD and suggest that pharmacological targeting of this pathway may offer therapeutic potential to correct the redox imbalance associated with the disorder.