Bridging exercise biology and immunometabolism: A novel irisin pathway toward next-generation metabolic and neurodegenerative therapies

Recent work by Mu et al. identifying irisin as a modulator of adipose tissue IL-33 and regulatory T cells introduces a new paradigm in immunometabolic biology, shifting attention from thermogenesis alone toward immune-stromal crosstalk as a determinant of metabolic health. By inducing IL-33 production in adipose mesenchymal stromal cells, irisin preserves ST2+ regulatory T cells (Tregs) in visceral adipose tissue, thereby restraining inflammation, improving insulin sensitivity, and promoting metabolic homeostasis. This mechanism expands the concept of exercise-induced metabolic protection by highlighting adipose tissue immune niches as critical targets of myokine action. In parallel, emerging evidence from preclinical models indicates that irisin-driven IL-33 signaling in subcutaneous adipose tissue contributes to thermogenic activation through mechanisms distinct from Treg-mediated immune regulation, highlighting depot-specific effects of this pathway. Beyond adipose tissue, irisin has emerged as a pleiotropic mediator with reported roles in glucose homeostasis, cardiovascular protection, and neurobiology. Importantly, accumulating evidence indicates that irisin may also exert neuroprotective effects, including the induction of brain-derived neurotrophic factor (BDNF), amyloid-β (Aβ) clearance, and α-synuclein degradation, thereby linking metabolic and neurodegenerative pathways. Although the findings of Mu et al. derive from preclinical models, they provide a conceptual model for therapeutic strategies aimed at reproducing selected benefits of exercise in obesity, metabolic and neurodegenerative disorders. Notably, these effects appear to depend on sustained irisin exposure in preclinical systems, supporting a role for irisin as a regulator of long-term immunometabolic homeostasis. Collectively, these observations position the irisin/IL-33/Treg axis as a promising link between exercise, adipose tissue immunity, and systemic metabolic regulation, suggesting that targeting immunometabolic circuits, rather than energy balance alone, may open new avenues for future therapeutic intervention.