RORA as a sex-specific molecular link in autism spectrum disorder: from transcriptional regulation to clinical phenotype across the lifespan.

RORA is a molecular hub in autism spectrum disorder (ASD) that integrate sex steroid signaling, neurodevelopmental gene regulation, circadian rhythm, immune function and metabolic homeostasis. Convergent evidence from postmortem brain, peripheral blood, methylation profiling, animal models and cellular studies indicates that RORA is frequently downregulated in ASD, disrupting downstream pathways involved in synaptogenesis, cortical development, aromatase activity and neuroimmune balance. RORA is bidirectionally regulated by sex hormone, where androgens suppresses and estrogens activates its expression, supporting frameworks for male-biased ASD risk and the female protective effect. RORA-aromatase feedback loop further biases toward androgen dominance and reduced estrogen-mediated protection. Across the lifespan, RORA deficiency may contribute to prenatal neurodevelopmental disruption, childhood circadian and metabolic abnormalities, inflammatory dysregulation and hormone-sensitive symptom fluctuations including overlap with PMDD. Although RORA is a promising biomarker and therapeutic candidate, prospective sex-stratified longitudinal studies are required to clarify its prognostic and treatment-stratification utility in ASD.