Irisin acts as an exercise mimetic to alleviate sedentary-induced osteoporosis by reprogramming macrophage-mediated inflammation via the HSP90-MAPK signaling axis.

Sedentary behavior induces bone loss partly through chronic low-grade inflammation, presenting a critical need for novel pharmacological interventions. Irisin, a cleaved product of Fibronectin type III domain-containing protein 5 (FNDC5), has emerged as a potential exercise mimetic, yet its therapeutic efficacy and precise molecular targets in osteoimmunology remain elusive. Here, we investigate the pharmacological potential of irisin in mitigating sedentary-induced osteoporosis by modulating macrophage-mediated inflammation. Population-based analyses first established systemic inflammation as a key mediator between physical inactivity and osteoporosis. Crucially, FNDC5 knockout mice failed to exhibit exercise-induced skeletal benefits, confirming the indispensable role of endogenous irisin in bone homeostasis. Mechanistically, in vitro assays revealed that exogenous irisin administration potently suppresses Tumor necrosis factor-alpha (TNF-α) production in Lipopolysaccharide (LPS)-stimulated macrophages by directly downregulating Heat shock protein 90 (HSP90) and subsequently inhibiting the Mitogen-activated protein kinase (MAPK) signaling cascade. Furthermore, conditioned media from irisin-treated or HSP90-silenced macrophages effectively reversed LPS-induced osteoclastogenesis and restored osteoblast differentiation-therapeutic effects that were completely abolished by HSP90 overexpression. In vivo, pharmacological administration of irisin in sedentary mice successfully improved bone microarchitecture, attenuated systemic inflammation, and rebalanced bone remodeling via the HSP90/MAPK axis, exhibiting comparable efficacy to physical exercise without detectable organ toxicity. Collectively, these findings identify the irisin-HSP90-MAPK axis as a novel therapeutic target, establishing irisin as a viable pharmacological exercise mimetic against inflammation-driven bone loss.