Exercise-derived irisin prevents bone loss via Nrf2 activation and inhibition of STING/NF-κB signaling.

Osteoporosis is driven in large part by excessive osteoclast-mediated bone resorption, and exercise-induced myokines such as irisin have emerged as potential modulators of bone remodeling, yet the mechanism by which irisin regulates osteoclastogenesis remains incompletely defined. Here, we integrated clinical analyses, mechanistic cell studies, and ovariectomized (OVX) mouse models to determine whether irisin protects against estrogen deficiency-induced bone loss and to delineate the underlying signaling axis. In 109 postmenopausal women, circulating irisin levels were positively associated with bone mineral density and inversely correlated with the bone resorption marker β-CTX. In vitro, irisin dose-dependently suppressed RANKL-induced osteoclast differentiation, F-actin ring formation, and resorption activity in bone marrow-derived macrophages, accompanied by downregulation of osteoclast marker genes and proteins. Mechanistically, network pharmacology and molecular docking, together with CETSA, co-immunoprecipitation, and immunofluorescence, supported a direct irisin-Nrf2 interaction; irisin stabilized Nrf2 and thereby restrained TRAF6-mediated K63-linked ubiquitination and activation of STING, resulting in attenuation of downstream NF-κB signaling. In vivo, irisin administration improved trabecular microarchitecture and reduced osteoclast number/activity in OVX mice, whereas these protective effects were largely abolished in Nrf2-deficient mice, indicating an Nrf2-dependent mechanism. Collectively, our findings identify an Irisin-Nrf2-STING/NF-κB axis that suppresses osteoclastogenesis and mitigates estrogen deficiency-induced bone loss, supporting irisin as a promising therapeutic candidate for osteoporosis.