Objective Liver cancer is ranked as the sixth most common neoplasm and the fourth leading cause of cancer death globally.There were 854,000 incident liver cancer cases and 810,000 deaths worldwide in 2015,and half of the cases and deaths occurred in China(1).Peroxisome proliferator-activated receptor-gamma(PPARγ)coactivator-1α(PGC1α)is a key regulator of mitochondrial biogenesis and respiration,it partners with about twenty nuclear factors such as PPARγ,HNF4,NRF1/2 and estrogen related receptor-α(ERRα)(2,3).The transcriptional coactivator PGC1α is involved in the carcinogenesis,progression,and metabolic state of cancer,and it plays critical role in cancer progression and metabolism(4-8).However,the regulatory role and underlying mechanisms of PGC1α in hepatocellular carcinoma(HCC)are unknown.Here,we tested the impact of PGC1α on HCC progression and metabolism.Methods We compared expression levels of PGC1α in paired HCC tissues and adjacent noncancerous liver tissues collected from patients at Eastern Hepatobiliary Surgery Hospital(EHBH),Second Military Medical University,Shanghai,China,between 2000 to 2003 by real-time polymerase chain reaction(PCR)(n=65),western blot(n=8),and immunohistochemistry(IHC)(n=74)analyses.The prognosis analysis was done using human HCC tissue microarray constructed with specimens from 233 patients with HCC who underwent curative resection between 1996 and 2001 at EHBH.In vitro and in vivo assays were performed to observe the biological function of PGC1α overexpression in HCCLM3 and MHCC97H cells,and PGC1α knockdown in HepG2 and SMMC7721 cells,including migration and invasion assay,cell viability,in vivo metastasis assay and so on.The mechanism that PGC1α inhibits HCC metastasis by suppressing Warburg effect was elucidated by RNA sequencing(RNA-seq),untargeted LC-MS assay,real-time PCR,western blot,measurement of ECAR and OCR,measurement of ATP,glucose,and lactate,TOP/FOPFLASH assay,and dual-luciferase reporter assay.Results In this study,we observed that the mRNA and protein levels of PGC1α were significantly downregulated in human HCC tissues compared with adjacent noncancerous liver tissues.A clinical study showed that the low levels of PGC1α expression were correlated with poor survival,vascular invasion,and larger tumor size.PGC1α inhibited the migration and invasion of HCC cells both in vitro experiment and in vivo mouse model.However,PGC1α did not significantly influence the proliferation of HCC cells.Mechanistically,transcriptomic and metabolomics analyses revealed that the reprogrammed glucose metabolism induced by PGC1α is involved in metastasis of HCC,PGC1α suppresses HCC progression by inhibiting the Warburg effect.Furthermore,we found that PGC1α suppressed Warburg effect through the downregulation of pyruvate dehydrogenase kinase isozyme 1(PDK1)in HCC cells.The gene set enrichment analysis(GSEA)and TOP/FOPFLASH reporter assay were performed in HCCLM3 cells with PGC1α overexpression,results showed that WNT/β-catenin signaling was significantly suppressed.It has been described that WNT/β-catenin signaling promotes aerobic glycolysis through PDK1 which is a direct WNT/β-catenin target gene in colon cancer cells(9).In HCC cells,we found that PGC1α-induced inhibition of PDK1 is mediated by inhibition of WNT/β-catenin signaling,and the activation of PPARγ is required for PGC1α-induced inhibition of WNT/β-catenin pathway and Warburg effect by increasing β-catenin degradation.Finally,IHC analysis in a cohort of 233 HCC patients who had undergone surgical resection showed that PGC1α negatively correlates with PDK1 and β-catenin expression.Conclusions We first found that low levels of PGC1α expression were associated with poor prognosis in HCC,and revealed molecular mechanism of PGC1α in metabolism and progression of HCC.PGC1α suppressed HCC cells metastasis by inhibiting the Warburg effect via regulating WNT/β-catenin/PDK1 axis,and the tumor suppressive activity of PGC1α depended on PPARγ.Our findings indicate that PGC1α may act as a candidate therapeutic target for HCC patients.