Pharmacological modulators targeting the NRF2 pathway in HCC and their impact on lipid peroxidation and ferroptosis.
| Compound | Model | Doses | NRF2 pathway targeting strategy | Effect on lipid peroxidation/NRF2 | Conclusion | Study |
|---|---|---|---|---|---|---|
| In vitro studies | ||||||
| CPT + sorafenib | HepG2 and Huh7 cells | CPT 1–5 μM + sorafenib 5 μM | CPT inhibits NRF2’s expression, synergizing with sorafenib to induce ferroptosis | ↓ NRF2 intracellular levels, ↑ lipid peroxidation | CPT synergizes with sorafenib to induce ferroptosis | Elkateb et al., 2023 [38] |
| Metformin + sorafenib | HCC cell lines, mouse xenograft | PPI 1–4 μM | Metformin + sorafenib inhibits p62-KEAP1-NRF2 pathway | ↓ NRF2’s translocation to the nucleus, ↑ ferroptosis with combo therapy | Reverses NRF2-driven resistance to sorafenib | Tang et al., 2022 [41] |
| Picropodophyllin (PPP) | In vitro and in vivo HCC models | PPP 2.5–10 μM | PPP inhibited the PI3K-AKT-NRF2 pathway | ↓ NRF2 target genes, ↑ lipid ROS; ferroptosis via iron overload | Induces ferroptosis through NRF2 inhibition | Zheng et al., 2025 [42] |
| Arsenic trioxide (ATO) | HCC cell lines | ML385 10 μM | ATO-induced ferroptosis enhanced by silencing NRF2 | ↑ Lipid ROS, MDA, Fe2+, ↑ NRF2 knockdown ferroptosis | Ferroptosis enhanced by NRF2 silencing | Huang et al., 2025 [43] |
| Tiliroside | HCC cell lines and tumor xenografts in nude mice | Not applicable | Tiliroside promotes the ubiquitination of NRF2 and sensitizes cells to ferroptosis inducers | ↓ NRF2 intracellular levels, ↑ lipid peroxidation, and enhanced ferroptotic cell death | Sensitizes HCC cells to ferroptosis inducers | Yang et al., 2023 [44] |
| Bavachin | Huh7 and HepG2 cells | Bavachin 20–40 μM | Bavachin mildly activates NRF2/HO-1 pathway | ↑ ROS, MDA, exceeding the protective effect of NRF2’s activation | Promotes ferroptosis via oxidative stress | Li et al., 2024 [45] |
| Brusatol | Cell lines and patient tissue | Brusatol 100 nM; sulforaphane 5 μM | NRF2-driven CYP4F11 expression promotes HCC and resistance | ↑ NRF2 inhibition sensitizes cells, ↑ lipid peroxidation | Suppresses HCC via CYP4F11-NRF2 inhibition | Chen et al., 2025 [39] |
| In vivo studies | ||||||
| DSF/Cu | HCC cell lines | DSF 1 μM + Cu 1 μM | DSF/Cu treatment elevates NRF2 as a compensatory response | ↑ Lipid peroxidation impairs mitochondrial homeostasis | Potentiated by NRF2 inhibition | Ren et al., 2021 [48] |
| Arenobufagi | HepG2 cells, nude mice | Arenobufagin 20 μM | Arenobufagin modulates p62-KEAP1-NRF2 to induce autophagy-dependent ferroptosis | ↓ NRF2 intracellular levels, ↑ MDA, lipid ROS | Induces autophagy-dependent ferroptosis | Yang et al., 2024 [46] |
| NSC48160 | HepG2, SMMC-7721 and BEL-7402 cells | NSC48160 36 μM | Disrupts TCA cycle metabolism and indirectly inhibits the NRF2-SLC7A11-GPX4 axis | ↑ Lipid peroxidation and ferroptosis, ↓ NRF2 expression, and its downstream effectors | Promotes ferroptosis via NRF2 suppression | Zhang et al., 2025 [47] |
This table is of the author’s own elaboration based on the review literature. This table summarizes in vitro and in vivo studies evaluating compounds that modulate the NRF2 pathway in HCC, including their models, doses, molecular mechanisms, effects on lipid peroxidation, and therapeutic implications in improving ferroptosis or overcoming drug resistance. AKT: protein kinase B; CPT: camptothecin; Cu: copper; DSF: disulfiram; GPX4: glutathione peroxidase 4; GSH: glutathione; HCC: hepatocellular carcinoma; HO-1: heme oxygenase-1; KEAP1: Kelch-like ECH-associated protein 1; MDA: malondialdehyde; NRF2: nuclear factor erythroid 2-related factor 2; p62: sequestosome 1; PI3K: phosphatidylinositol 3-kinase; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; TCA: tricarboxylic acid.