Targeting exercise triggered irisin for therapeutic intervention of autism-associated social anxiety

Autism spectrum disorder (ASD) is frequently complicated by debilitating social anxiety, which exacerbates social impairments and reduces quality of life. This review explores the therapeutic potential of exercise-induced irisin, a myokine released during physical activity, in mitigating ASD-associated social anxiety. Irisin, derived from the cleavage of skeletal muscle FNDC5 protein, crosses the blood-brain barrier and modulates key neurobiological pathways implicated in ASD. It enhances neurogenesis and synaptic plasticity via BDNF upregulation, suppresses neuroinflammation by reprogramming microglia and reducing pro-inflammatory cytokines, and normalizes HPA axis hyperactivity to reduce stress responses. Preclinical evidence demonstrates irisin's efficacy in improving social behaviour and reducing anxiety in ASD rodent models, while clinical studies correlate exercise with reduced anxiety in ASD individuals, though direct irisin measurements remain limited. Despite heterogeneity in exercise responsiveness and adherence challenges in ASD populations, irisin represents a promising endogenous mediator for novel therapeutic strategies, including optimized exercise regimens and pharmacological mimetics.