Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD) depletion, targeting the NAD⁺ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD⁺ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD+ and subsequently activating the SIRT1–HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high-risk chondrosarcoma patient subgroup characterized by the upregulation of NAD⁺ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2α transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD⁺. We provide system level guidelines to develop therapeutic strategies for chondrosarcomas.

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