Irisin and anxiety-like behaviors: Mechanistic integration of peripheral-central crosstalk, neuroinflammation, and neural plasticity.

Anxiety-related disorders are highly prevalent and persistently difficult to treat, largely due to insufficient understanding of peripheral-central regulatory mechanisms governing emotional behaviors. Irisin, an exercise-dependent myokine, serves as a critical peripheral-to-central signaling mediator modulating brain function and anxiety-like behavioral phenotypes. This review systematically integrates current preclinical evidence illustrating how irisin regulates anxiety through multi-level neural mechanisms. Irisin suppresses microglial NF-κB/STAT3-mediated neuroinflammation, enhances prefrontal-hippocampal synaptic plasticity via BDNF upregulation and AMPK/mTOR-related autophagy, and improves gut-brain axis homeostasis by stabilizing intestinal barrier integrity and reshaping microbial composition. Crucially, we propose a context-dependent therapeutic window model to reconcile contradictory pro-anxiogenic and anxiolytic findings across stress severity and pathological stages, resolving existing controversies in this field. We further summarize key unresolved limitations, including ambiguous central receptor identity, peripheral-central dissociation and sex-dependent heterogeneity. This work provides an integrated mechanistic framework linking muscular metabolic signals to affective circuit regulation, offering novel translational perspectives for anxiety behavioral modulation and targeted therapeutic development.