A study reveals that the serine synthesis pathway (SSP) is essential for osteoclast differentiation through epigenetic regulation of NFATc1 expression. The SSP, which generates serine and glycine, is transiently activated during early osteoclastogenesis. This activation is necessary for the production of α-ketoglutarate (αKG), which is critical for histone demethylases that remove repressive histone methylation marks at the NFATc1 gene locus, thereby inducing NFATc1 expression and osteoclast maturation. Deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH) in osteoclast progenitors impairs differentiation and increases bone mass. Pharmacological inhibition of PHGDH abrogates bone loss in a mouse model of postmenopausal osteoporosis by blocking bone resorption. The study shows that SSP-derived αKG is crucial for osteoclast differentiation, as it is required for the epigenetic regulation of NFATc1 expression. The findings suggest that targeting the SSP could be a therapeutic strategy to prevent osteoporotic bone loss. The study also highlights the metabolic-epigenetic coupling mechanism that directs osteoclast differentiation and underscores the importance of the SSP in maintaining bone homeostasis. The results indicate that the SSP is essential for osteoclastogenesis, as PSAT1 generates αKG that is necessary for proper differentiation. The study provides insights into the molecular mechanisms that govern osteoclast formation and activity, which could lead to the development of novel anti-osteoporosis drugs.A study reveals that the serine synthesis pathway (SSP) is essential for osteoclast differentiation through epigenetic regulation of NFATc1 expression. The SSP, which generates serine and glycine, is transiently activated during early osteoclastogenesis. This activation is necessary for the production of α-ketoglutarate (αKG), which is critical for histone demethylases that remove repressive histone methylation marks at the NFATc1 gene locus, thereby inducing NFATc1 expression and osteoclast maturation. Deletion of the rate-limiting enzyme phosphoglycerate dehydrogenase (PHGDH) in osteoclast progenitors impairs differentiation and increases bone mass. Pharmacological inhibition of PHGDH abrogates bone loss in a mouse model of postmenopausal osteoporosis by blocking bone resorption. The study shows that SSP-derived αKG is crucial for osteoclast differentiation, as it is required for the epigenetic regulation of NFATc1 expression. The findings suggest that targeting the SSP could be a therapeutic strategy to prevent osteoporotic bone loss. The study also highlights the metabolic-epigenetic coupling mechanism that directs osteoclast differentiation and underscores the importance of the SSP in maintaining bone homeostasis. The results indicate that the SSP is essential for osteoclastogenesis, as PSAT1 generates αKG that is necessary for proper differentiation. The study provides insights into the molecular mechanisms that govern osteoclast formation and activity, which could lead to the development of novel anti-osteoporosis drugs.