Natural products target the NRF2-ferroptosis axis in hepatocellular carcinoma: tumor sensitization versus hepatoprotection

Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality. First-line systemic therapy is now led by immune checkpoint inhibitor (ICI)-based regimens, notably atezolizumab plus bevacizumab and durvalumab plus tremelimumab, whereas sorafenib and lenvatinib are used mainly when immunotherapy is unsuitable and in later lines; resistance limits the durability of both strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, offers a potential strategy for overcoming this resistance. Nuclear factor erythroid 2-related factor 2 (NRF2) is a central but context-dependent regulator of this vulnerability. Transient NRF2 activation protects non-transformed hepatocytes from oxidative injury, whereas constitutive activation in HCC reinforces SLC7A11-and GPX4-dependent antioxidant defenses, promotes immune escape, and supports drug resistance. This mini-review evaluates how natural products and related formulations modulate this dual program. Polyphyllin I, tiliroside, ponicidin, picropodophyllin, curcumin, esculetin, sappanone A, and decursin act at distinct upstream nodes but converge on suppression of the p62-KEAP1-NRF2 pathway or its SLC7A11/GPX4 effectors, thereby restoring ferroptotic sensitivity in preclinical HCC models. In contrast, ginsenoside Rg1, thymoquinone, and hinokitiol activate NRF2 in models of non-malignant liver injury. Because the FSP1-CoQ10 and DHODH systems defend membranes against phospholipid peroxidation independently of GPX4, residual activity in these parallel arms can limit the efficacy of agents directed at the NRF2-SLC7A11-GPX4 axis. These findings support tumor-selective NRF2 modulation rather than indiscriminate systemic inhibition. Biased disruption of the KEAP1-p62 interaction and tumor-targeted nucleic-acid delivery provide proof of concept, but translation is constrained by limited pharmacokinetic, target-engagement, toxicologic, and clinical evidence.