Curcumin exerts distinct anti-tumor effects mediated by NRF1α from NRF2 via metabolic reprogramming in hepatocellular carcinoma (HepG2).

NRF1α and NRF2, two CNC-bZIP transcription factors, regulate redox homeostasis and metabolic stability, forming a precisely coordinated regulatory network in HCC characterized by functional complementarity and directional antagonism. Although curcumin (CUR), a dietary polyphenol, exerts pleiotropic anti-cancer effects, its clinical application is limited by low bioavailability and undefined molecular targets. This study hypothesized that CUR acts through differential regulation of NRF1α/NRF2-mediated signaling, with NRF1α as the primary effector in HCC. Firstly, we confirmed direct CUR-NRF1α interaction, and CUR stabilizes NRF1α through suppressing proteasomal degradation. Subsequently experiments, using a panel of isogenic HepG2 cell lines (wild-type, NRF1α-∕-, NRF2-∕-) and xenograft models, we characterized the dose-dependent effects of CUR on NRF1α expression and systematically compared its downstream pathways involved in oxidative stress resistance and metabolic regulation. CUR exhibited genotype-dependent biphasic effects: it synergistically activated both NRF1α and NRF2 in WT cells, but paradoxically inhibited hyperactive NRF2 in NRF1α-deficient cells. NRF1α mediated the core tumor-suppressive functions via metabolic reprogramming and alleviation of oxidative stress, whereas NRF2 contributed to residual protective effects in the absence of NRF1α. Notably, the anti-tumor efficacy of CUR was largely dependent on intact NRF1α signaling. In xenograft models, CUR showed modest single-agent activity but induced synthetic lethality in NRF1α-deficient tumors by inhibiting NRF2. Collectively, NRF1α acts as the primary effector of CUR in HCC, offering new mechanistic insights. These findings support the development of NRF1α-selective CUR derivatives and highlight NRF1 expression as a candidate predictive biomarker.