SMAD4 and hepatocellular carcinoma: While NRF1 is known to collaborate with transcription coactivator PGC1α to regulate target gene transcription in mitochondrial biogenesis, it’s interesting that PGC1α plays a suppressive role in HCC but NRF1 plays a promotive role.[37, 38] Considering that NRF1 can also act as a transcription cofactor of SMAD4 and that PGC1α also functions as transcription coactivator of ERRα, PPARγ etc.,[39] we hypothesize that in HCC the specific transcription pattern makes NRF1 and PGC1α not functionally integrated, which leads to the final difference in their function.