biostudies-literatureWang HNational Natural Science Foundation of China169https://www.ebi.ac.uk/biostudies/studies/S-EPMC9548188biostudies-literatureUnknown12(1)Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLCCell & bioscienceInhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity.PMC9548188819027348207296981772859Hua YJin XShen JWang CMa XWang HSun WXu JSun MZhang TZhang YZan PWang ZfalseInhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity.Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLC2022-01-01T00:00:00Z2022 Oct2026-06-01T02:11:08.522Z2025-02-19T01:28:38.555ZS-EPMC95481883620919710.1186/s13578-022-00900-9