The NRF2 signaling pathway in hepatocellular carcinoma: dual roles, epigenetic reprogramming, and therapeutic opportunities in metabolic vulnerability
TL;DR
NRF2-related metabolic pathways and redox defense systems exhibit potential metabolically targetable vulnerabilities, providing a theoretical basis for combined induction of ferrocytosis and metabolic intervention in HCC.
Abstract
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignant tumor with a poor prognosis; its onset and progression are closely associated with persistent oxidative stress and metabolic reprogramming. Nuclear factor E2-related factor 2 (NRF2), as a key transcription factor regulating redox homeostasis, exerts a cytoprotective effect during chronic liver injury by inducing the expression of antioxidant and detoxification genes; however, following tumor formation, it may undergo abnormal, sustained activation, thereby contributing to metabolic adaptation and treatment resistance in HCC. Based on evidence from existing basic and translational research, this review systematically integrates the multilevel regulatory networks of NRF2 in HCC, including the classical KEAP1–NRF2 ubiquitination and degradation pathway, the p62-mediated non-classical activation mechanism, and the cross-regulation of metabolic stress signaling pathways such as AMPK–mTOR. Based on this, we summarize the stage-dependent dual role of NRF2 in HCC progression: in early-stage chronic liver injury, it primarily limits oxidative stress and DNA damage; whereas in advanced tumors, it enhances tumor cell survival and promotes invasion, metastasis, and multidrug resistance through metabolic reprogramming, such as by promoting glucose metabolism, glutathione synthesis, and the pentose phosphate pathway. Furthermore, NRF2 enhances resistance to ferrocytosis by reshaping the GSH–GPX4 axis and the iron homeostasis network, and may participate in the regulation of the tumor immune microenvironment, thereby collectively shaping the treatment-resistant characteristics of HCC. Based on these context-dependent changes, NRF2-related metabolic pathways and redox defense systems exhibit potential metabolically targetable vulnerabilities, providing a theoretical basis for combined induction of ferrocytosis and metabolic intervention. Overall, NRF2 exhibits significant context-dependence and dual biological effects in HCC; its precise regulatory mechanisms and clinical translational value remain to be further validated.