This study investigates the role of glutamine (Glu) in osteoclast differentiation and function, and its regulation by IL-17. Glu is essential for osteoclast differentiation and function, as its deprivation or pharmacological inhibition with V9302 (a Glu transporter ASCT2 inhibitor) suppresses osteoclast differentiation and bone resorption. In vivo treatment with V9302 improves ovariectomy (OVX)-induced bone loss. Mechanistically, RNA sequencing and in vitro/in vivo experiments show that Glu mediates IL-17's role in promoting osteoclast differentiation and regulating energy metabolism. IL-17 treatment exacerbates OVX-induced bone loss, which is dependent on Glu or its downstream metabolite α-keto-glutarate (α-KG). Targeting the IL-17-Glu-energy metabolism axis may be a potential therapeutic strategy for osteoporosis and other IL-17-related diseases.This study investigates the role of glutamine (Glu) in osteoclast differentiation and function, and its regulation by IL-17. Glu is essential for osteoclast differentiation and function, as its deprivation or pharmacological inhibition with V9302 (a Glu transporter ASCT2 inhibitor) suppresses osteoclast differentiation and bone resorption. In vivo treatment with V9302 improves ovariectomy (OVX)-induced bone loss. Mechanistically, RNA sequencing and in vitro/in vivo experiments show that Glu mediates IL-17's role in promoting osteoclast differentiation and regulating energy metabolism. IL-17 treatment exacerbates OVX-induced bone loss, which is dependent on Glu or its downstream metabolite α-keto-glutarate (α-KG). Targeting the IL-17-Glu-energy metabolism axis may be a potential therapeutic strategy for osteoporosis and other IL-17-related diseases.