TABLE 1.
The regulators of ferroptosis in HCC.
| Gene/Axis/Compound/Drug | Mechanism | Target | Influence to ferroptosis | References |
|---|---|---|---|---|
| Ubiquitin-like Modifier Enzyme 1 (UBA1) | Inhibit NRF2 expression by inhibiting of UBA1 | NRF2 | - | Shan et al. (2020) |
| Disulfiram (DSF) | DSF inhibits the signaling pathways of NRF2 and MAPK kinase | NRF2 | + | Ren et al. (20211021) |
| p62 | p62 can down-regulate Keap1 expression and reduce NRF2 degradation | Keap1 | - | Sun et al. (2016a) |
| Xanthine Oxidoreductase (XOR) | XOR can down-regulate NRF2 expression | Keap1 | + | Sun et al. (2020) |
| Tripartite motif-containing 25 (TRIM25) | TRIM25 can activate NRF2 | Keap1 | - | Liu et al. (2020) |
| Malic enzymes (ME) | Transcriptionally activating ME1 by NRF2 when cells encounter further episodes of ROS insult | induced by NRF2 | Lee et al. (2021) | |
| Sigma-1 receptor (S1R) | S1R can regulate NRF2 thus inhibiting ROS accumulation | NRF2 | - | Bai et al. (2019) |
| Catenin beta-1 (CTNNB1) | CTNNB1 may have synergistic effect with NRF2 mutation | NRF2 | Unknown | Zavattari et al. (2015); Tao et al. (2021) |
| miR-101 (miRNA) | Target the 3′-UTR of NRF2 and negatively regulate NRF2 | NRF2 | + | Gao et al. (2017); Raghunath et al. (2018) |
| miR-144 (miRNA) | Activation of Nrf2 | NRF2 | - | Raghunath et al. (2018) |
| miR-340 (miRNA) | Target at the 3′-UTR of NRF2 and negatively regulate NRF2 | NRF2 | + | Shi et al. (2014); Raghunath et al., 2018) |
| miR-122 (miRNA) | Inhibited by NRF2 | Inhibited by NRF2 | Unknown | Aydin et al. (2019) |
| miR-129-3p (miRNA) | Induced by NRF2 | Induced by NRF2 | Unknown | Sun et al. (2019) |
| miR-141 (miRNA) | Upregulate NRF2 | Keap1 | - | Raghunath et al. (2018) |
| miR-200a (miRNA) | Increase NRF2 and inhibit TFR1 expression | Keap1 | - | Greene et al. (2013); Raghunath et al. (2018) |
| Kral (lncRNA) | Induce Keap1 to regulate NRF2 | Keap1 | + | Wu et al. (2018) |
| Glutathione S-transferase zeta 1 (GSTZ1) | Inhibit NRF2/GPX4 axis | NRF2 | + | Wang et al. (2021a) |
| Quiescin sulfhydryl oxidase 1 (QSOX1) | Inhibit NRF2 | NRF2 | + | Sun et al. (2021) |
| miR-200b (miRNA) | Adjust ferritin heavy chain 1(FtH1) and ferritin light chain (FtL) | Ferritin | Unknown | Greene et al. (2013) |
| miR-122 (miRNA) | Reduce iron by adjusting Nocturnin | Nocturnin | Unknown | Zhang et al. (2020) |
| PVT1 (lncRNA) | Increase lipid peroxidation and iron deposition in vivo and in vitro | TFR1 | + | Lu et al. (2020) |
| miR-152 (miRNA) | Inhibit TFR1 expression | TFR1 | - | Kindrat et al. (2016) |
| miR-22 (miRNA) | Inhibit TFR1 expression | TFR1 | - | Greene et al. (2013) |
| miR-320 (miRNA) | Inhibit TFR1 expression | TFR1 | - | Greene et al. (2013) |
| miR-107 (miRNA) | Inhibited by iron | Zou et al. (2016) | ||
| miR-30d (miRNA) | Inhibited by iron | Zou et al. (2016) | ||
| Formosaanin C | Inducing ferritinophagy and lipid ROS formation | / | + | Lin et al. (2020) |
| CDGSH iron sulfur domain2 (CISD2) | Excessive iron ion accumulation | Fe | - | Li et al. (2021b) |
| O-GlcNAcylation | Increase the iron concentration through transcriptional elevation of TFRC | TRFC | + | Zhu et al. (2021) |
| Solasonine | Increase lipid ROS levels by suppression of GPX4 and GSS | GPX4 | + | Jin et al. (2020) |
| Heteronemin | Decrease GPX4 expression and induced the formation of ROS | GPX4 | + | Chang et al. (2021) |
| Selenoproteins | Constitute GPX4 | GPX4 | - | Ingold et al. (2018) |
| Sigma-1 receptor (S1R) | Inhibit the expression of GPX4 | GPX4 | - | Bai et al. (2019) |
| Circ-interleukin-4 receptor (CircIL4R) | As a miR-541-3p sponge to regulate its target GPX4 | GPX4 | - | Xu et al. (2020) |
| Ketamine | Decrease expression of lncPVT1 (directly interacted with miR-214-3p to impede its role as a sponge of GPX4) and GPX4 | GPX4 | + | He et al. (2021) |
| Legumain | Promote chaperone-mediated autophagy of GPX4 | GPX4 | + | Chen et al. (2021) |
| vitamin D receptor (VDR) | Transregulation of GPX4 | GPX4 | - | Hu et al. (2020) |
| Ceruloplasmin (CP) | Accumulation of intracellular ferrous iron (Fe2+) and lipid ROS | Fe | - | Shang et al. (2020) |
| miR-22 (miRNA) | Increase ROS | SIRT-1 | + | Pant et al. (2017) |
| miR-92 (miRNA) | Increase ROS | unknown | + | Cardin et al. (2012) |
| miR-145 (miRNA) | Elimination of insulin-induced PKM2 and ROS elevation | PKM2 | - | Li et al. (2014) |
| miR-222 (miRNA) | Unknown | ER (endoplasmic reticulum) | - | Dai et al. (2010) |
| Let-7 (miRNA) | Directly acts on the 3′-UTR of Bach1 and negatively regulates expression of this protein, and thereby up-regulates modulation of heme oxygenase 1 (HMOX1) gene expression | Heme oxygenase-1 | - | Hou et al. (2012) |
| miR-221 (miRNA) | Unknown | ER | - | Dai et al. (2010) |
| miR-21 (miRNA) | Increase ROS | unknown | + | Shu et al. (2016) |
| miR-181 (miRNA) | Increase ROS | Unknown | + | Zhang et al. (2020) |
| miR-200a-3p (miRNA) | Inhibite p38/p53/miR-200 feedback loop and increased ROS | p53 | + | Xiao et al. (2015) |
| miR-125b (miRNA) | Increase ROS | HK2 | + | Li et al. (2017) |
| miR-26a (miRNA) | Regulate fatty acid and cholesterol homeostasis and decreasing ROS | Triglyceride, totalcholesterol, malondialdehyde | - | Ali et al. (2018) |
| miR-885-5p (miRNA) | Induce TIGAR (TP53-induced glycolysis and apoptosis regulator)expression through a p53-independent pathway and decreasing ROS | TIGAR | - | Zou et al. (2019) |
| miR-150-3p (miRNA) | Induced by ROS | / | / | Wan et al. (2017) |
| miR-1915-3p (miRNA) | Induced by ROS | / | / | Wan et al. (2017) |
| miR-34a-3p (miRNA) | Induced by ROS | / | / | Beccafico et al. (2015) |
| miR-34a-5p (miRNA) | Induced by ROS | / | / | Wan et al. (2017) |
| miR-638 (miRNA) | Induced by ROS | / | / | Wan et al. (2017) |
| H19 (ncRNA) | Decrease ROS | MAPK/ERK signaling pathway | - | Ding et al. (2018) |
| GABPB1-AS1 (lncRNA) | Downregulate the gene encoding Peroxiredoxin-5 (PRDX5) peroxidase and the eventual suppression of the cellular antioxidant capacity | / | + | Qi et al. (2019) |
| miR-18a (miRNA) | Downregulate the expression of Glutamate-Cysteine Ligase Subunit Catalytic (GCLC), the rate-limiting enzyme of GSH synthesis | GSH | + | Anderton et al. (2017) |
| miR-152 (miRNA) | Reduce GSH levels by targeting Glutathione S-transferase | GSH | + | Huang et al. (2010) |
| miR-503 (miRNA) | Unknown | GSH | + | Wang et al. (2014) |
| Neat1 (lncRNA) | Increase GST to increase GSH consumption | GST | + | Wang et al. (2018) |
| Metallothionein-1G (MT-1G) | Induce depletion of GSH | GSH | - | Sun et al. (2016b) |
| Deleted in azoospermia-associated protein 1 (DAZAP1) | Interact with the 3′UTR (untranslated region) of SLC7A11 mRNA and positively regulate its stability | SLC7A11 | - | Wang et al. (2021b) |
| Transforming growth factor β1 (TGF-β1) | Upregulate of Smad3 inhibits SLC7A11 expression | SLC7A11 | + | Kim et al. (2020) |
| sulfasalazine | Inhibit SLC7A11 | SLC7A11 | + | Song et al. (2017) |
| Actinomycin D | Inhibit of SLC7A11 expression by inhibition of CD133 synthesis | SLC7A11 | + | Song et al. (2017) |
| Circ0097009 (circRNA) | Regulate of SLC7A11 expression by expression of miR-1261 | SLC7A11 | - | Lyu et al. (2021) |
| METTL14 | SLC7A11 mRNA was modified at 5′UTR and degraded | SLC7A11 | + | Fan et al. (2021) |
| transcription factors YAP/TAZ | Induce the expression of SLC7A11 | SLC7A11 | - | Gao et al. (2021) |
| IFN-γ | Down-regulate the mRNA and protein levels of SLC3A2 and SLC7A11 | SLC7A11 | + | Kong et al. (2021) |
| activating transcription factor 3 (ATF3) | Bind to the SLC7A11 promoter and repressing SLC7A11 expression in a p53-independent manner | SLC7A11 | + | Wang et al. (2020) |
| miR-182-5p and miR-378a-3p (miRNA) | Directly bind to the 3′UTR of GPX4 and SLC7A11 mRNA, downregulation of GPX4 and SLC7A11 | GPX4, SLC7A11 | + | Ding et al. (2020) |
| LINC00618 (lncRNA) | Increase the levels of lipid ROS and iron, decreasing the expression of SLC7A11 | ROS,SLC7A11 | + | Wang et al. (2021c) |
| microRNA-17-5p (miRNA) | Activate the p38 MAPK pathway, which in turn facilitates the phosphorylation of HSPB1 | HSPB1 | unknown | Yang et al. (2010) |
| heat shock protein beta-1 (HSPB1) | Reduce iron-mediated production of lipid ROS | ROS | - | Sun et al. (2015) |
| protein kinase p38α (Mapk14) | Decrease the expression of HSPB1 to reduce the accumulation of intracellular ROS | HSPB1 | + | Sakurai et al. (2013) |
| dual specificity phosphatase 1 (DUSP1) | Inhibit the phosphorylation of P38 MAPK and HSPB1 | HSPB1 | + | Hao et al. (2015) |
| Astragalus | Directly down-regulate MT1G | MT1G | + | Liu et al. (2021b) |
| microRNA-205 and microRNA-211-5p (miRNA) | Target the 3ʹUTR of ACSL4 inhibits ACSL4 expression at mRNA and protein levels | ACSL4 | - | Cui et al. (2014); Qin et al. (2020) |
| Lactic acid | Produce sterol regulatory element binding protein 1 (SREBP1) and downstream stearoyl-coA desaturase-1 (SCD1) to enhance the production of iron-resistant monounsaturated fatty acids (PUFA). SCD1 acts synergistically with acyl-CoA synthase 4 (ACSL4) | ACSL4,PUFA | - | Zhao et al. (2020) |
| NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1) | React with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity | PUFA | + | Yan et al. (2021) |
| DJ-1/PARK7 (cancer-associated protein) | DJ-1 depletion inhibits the transsulfuration pathway by disrupting the formation of the S-adenosyl homocysteine hydrolase tetramer and impairing its activity | homocysteine | - | Cao et al. (2020) |
| hydroxycarboxylic acid receptor 1 (HCAR1)/monocarboxylate transporter 1 (MCT1) | Enhance the production of anti-ferroptosis monounsaturated fatty acids | MUFA | - | Zhao et al. (2020) |