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Targeting energy metabolism holds the potential to effectively treat a variety of malignant diseases, and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a key regulator of energy metabolism. However, PGC1α′s role in cancer, especially in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we reported that PGC1α was significantly downregulated in HCC cell lines and specimens. Moreover, reduced expression of PGC1α in tumor cells was correlated with poor prognosis. PGC1α overexpression substantially inhibited cell proliferation and induced apoptosis in vitro and in vivo. On the contrary, the knockdown of PGC1α produced the opposite effect. The mechanism was at least partially due to the upregulation of mitochondrial pyruvate carrier 1 (MPC1) caused by PGC1α, which promoted mitochondrial biogenesis by binding to nuclear respiratory factor 1 (NRF1). Consequently, the production of cellular reactive oxygen species (ROS) caused by mitochondrial oxidation was elevated above a critical threshold for survival. Furthermore, we found that PGC1α could enhance the antitumor activity of sorafenib and doxorubicin in HCC through ROS accumulation-mediated cell death. These results indicate that PGC1α/NRF1-MPC1 axis is involved in HCC progression and could be a promising target for HCC treatment. Image 1 • Low expression of PGC1α and MPC1 was associated with the poor prognosis of HCC. • PGC1α and MPC1 could inhibit HCC cell proliferation and induce apoptosis. • PGC1α/NRF1-MPC1 axis activates mitochondrial biogenesis and drives ROS production. • PGC1α/NRF1-MPC1 axis attenuates HCC progression. • PGC1α could enhance the sensitivity to sorafenib/doxorubicin treatment in HCC. [ABSTRACT FROM AUTHOR]