OXCT1 Regulates NF-κB Signaling Pathway Through β-Hydroxybutyrate-Mediated Ketone Body Homeostasis

Ketone bodies are small lipid-derived molecules,comprising acetone,acetoacetate(Ac Ac)and β-hydroxybutyrate(β-HB).In cancer cells,ketone bodies are used as alternative fuel for cancer cells to support survival and proliferation under stressed conditions.3-oxoacid Co A-transferase 1(OXCT1)is a key enzyme in ketone body metabolism that catalyzes the transfer of coenzyme A from succinyl-Co A to acetoacetate to generate acetoacetyl coenzyme A.Then,acetoacetyl coenzyme A is cleaved to acetyl-Co A,and the latter enters the TCA cycle.Recently,several studies demonstrate that OXCT1 is overexpressed in hepatoma,breast cancer,and prostate cancer,and the expression levels of OXCT1 are correlated with tumor malignancy.However,the function and underlying mechanism of OXCT1 in tumorigenesis remains largely unknow.In this study,we found that OXCT1 regulated SREBP1-TRIM21-NF-κB signaling axis through ketone body homeostasis.Mechanistically,we demonstrated that OXCT1 could control the homeostasis ofβ-hydroxybutyrate(β-HB),which acted as a signaling metabolite to activate sterol regulatory element binding protein 1(SREBP1).As a transcription factor,SREBP1 binds to the promoter of E3 ubiquitin ligase TRIM21 and enchances its trancription,and the latter mediated the ubiquitination of NF-κB.Furthermore,we found that OXCT1 promotes tumor growth in xenograft model.Taken together,these findings highlight a previously unappreciated mechanism for activation of NF-κB signaling by OXCT1 and ketone body homeostasis,and demonstrate that targeting OXCT1 can inhibit oncogenic transformation.