biostudies-literatureSuh JMinistry of Trade, Industry and EnergyMinistry of EducationInstitute for Basic ScienceKorea Drug Development FundKorea Health Industry Development InstituteMinistry of Health and WelfareMinistry of Science, ICT and Future PlanningNational Research Foundation of Korea101342https://www.ebi.ac.uk/biostudies/studies/S-EPMC10829737biostudies-literatureUnknown5(1)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 Cell reports. MedicineDecoupling NAD⁺ metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2α axis.PMC10829737IBS-R008-D1RS-2023-00213119NRF-2020R1A2C2012300RS-2023-00217266HI21C1218NRF-2023R1A2C30038642021RIS-001NRF-2020R1C1C1011369NRF-2021R1I1A1A01059250Min JKim HYeon HJKang HGKim YJSuh JWu MRHemberg MKim JHScimeca LfalseDecoupling NAD⁺ metabolic dependency in chondrosarcoma by targeting the SIRT1-HIF-2α axis.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 2024-01-01T00:00:00Z2024 Jan2026-07-15T04:38:40.47Z2024-11-14T14:43:17.479ZS-EPMC108297373812853410.1016/j.xcrm.2023.101342