Molecular insights for targeting the Nrf1 pathway in hepatocellular carcinoma

INTRODUCTION: Nuclear factor erythroid 2-related factor 1 (Nrf1, encoded by NFE2L1) plays a central role in maintaining cellular homeostasis, basal redox balance, and mitochondrial quality control and its function. Recent studies have revealed that Nrf1 assumes complex, even opposing roles in functioning both as a tumor-suppressor and otherwise, also as an unconvincing driver of Hepatocellular carcinoma (HCC) progression through certain oncogenic pathways and redox stress adaptation. AREAS COVERED: This mini-review systematically outlines the molecular-cellular regulatory network of Nrf1 and further elucidates its functional divergence and synergy with Nrf2 (encoded by NFE2L2) in HCC. EXPERT OPINION: Research on Nrf1 in the field of HCC has evolved from describing its basic pathophysiological functions to a systematic analysis of its putative dual roles in tumor initiation and progression, its isoform specificity, complex regulatory networks, and therapeutic potentials. Targeting Nrf1 for hepatocellular carcinoma therapy is just facing multiple challenges. Future research priorities will focus on: elucidating Nrf1 isoform specificity and post-translational modification profiles, developing a molecular classification system based on the Yin (Nrf1)-Yang (Nrf2) balance and even non-equilibrium steady-states, and screening for Nrf1α/TCF11-targeting modulators or activators to stimulate homeostatic anti-cancer defense mechanisms.