Table 13 Small molecule compounds target dysregulated epigenetic and posttranslational mechanisms to induce ferroptosis in cancer
Cancer | Compounds | Modification | Targets | Biological functions | Ref |
|---|---|---|---|---|---|
HCC | Tiliroside | Ubiquitination | p62/Keap1/Nrf2 | Tiliroside is a potent TBK1 inhibitor and functions as a sensitizer of sorafenib in HCC treatment by targeting TBK1 to induce ferroptosis through decreasing the phosphorylation p62 and the affinity of p62 for Keap1 and promoting Keap1-mediated Nrf2 ubiquitination and degradation | |
HCC | Corosolic acid | Ubiquitination | HERPUD1 | CA can increase sensitivity to ferroptosis through inhibiting GSH synthesis via HERPUD1, which reduced the ubiquitination of the GSS-associated E3 ubiquitin ligase MDM2, promoting ubiquitination of GSS, thereby inhibiting GSH synthesis to increase ferroptosis susceptibility | |
HCC | DHA | Ubiquitination | PEBP1 | DHA induced ferroptosis by promoting the formation of PEBP1/15-LO and promoting cell membrane lipid peroxidation. DHA promote PEBP1 protein expression through inhibition of its ubiquitination degradation. | |
HCC | Polyphyllin VI | Phosphorylation | STAT3 | Polyphyllin VI induces the ferroptosis through inhibiting STAT3 phosphorylation, which inhibits GPX4 expression. | |
HCC | Anisomycin | Phosphorylation | p38MAPK | Anisomycin activates p38MAPK to induce ferritinophagy through the phosphorylation of histone H3 on serine 10 (p-H3S10). | |
NSCLC | Bufotalin | Ubiquitination | GPX4 | Bufotalin induces ferroptosis by facilitating the ubiquitination and degradation of GPX4. | |
NSCLC | Sanguinarine | Ubiquitination | GPX4 | Sanguinarine triggered ferroptosis through decreasing the protein stability of GPX4 through E3 ligase STUB1-mediated ubiquitination and degradation of endogenous GPX4. | |
NSCLC | Selenite | Methylation | p38MAPK | Selenite induces ferroptosis through activating p38-ATF4-DDIT3 axis in the unfolded protein response. Selenite also altered cellular DNA methylation machinery through downregulating DNMT1 and upregulating TET1, though not as a major mechanism of its activity. Low-dose selenite synergized with osimertinib in EGFR-mutant H1975, and with adagrasib in KRAS-mutant H358, with stronger synergism observed in H1975. | |
BC | Eupaformosanin | Ubiquitination | p53 | Eupaformosanin significantly inhibited the viability of triple-negative breast cancer (TNBC) cells through inducing ferroptosis via ubiquitination of mutant p53. | |
BC | DMOCPTL | Ubiquitination | GPX4 | DMOCPTL induce ferroptosis through ubiquitination of GPX4. | |
BC | NN3 | Ubiquitination | p53/SLC7A11 | NN3 triggers ubiquitination and proteasome-mediated degradation of PARP1. NN3 exhibited a unique antitumor mechanism in p53-positive breast cancer cells that effectively promoted ferroptosis by downregulating the SLC7A11 pathway. | |
BC | Ketamine | Acetylation | KAT5 | Ketamine induces ferroptosis through inhibiting the expression of GPX4 by attenuating KAT5 on the promoter region of GPX4, repressing the enrichment of histone H3 lysine 27 acetylation (H3K27ac) and RNA polymerase II (RNA pol II) | |
GBM | ALZ003 | Ubiquitination | Androgen receptor | ALZ003 induces FBXL2-mediated AR ubiquitination and degradation. ALZ003 significantly inhibited the survival of glioblastomathrough inducing ferroptosis | |
Glioma | Paeoniflorin | Ubiquitination | NEDD4L/STAT3 | Paeoniflorin might function as an effective drug for glioma by inducing ferroptosis via upregulation of NEDD4L and mediates the ubiquitination of STAT3 repression of Nrf2, GPX4 | |
GBM | Myrislignan | Phosphorylation | NF-κB | Myrislignan inhibited the activation of NF-κB signaling by blocking the phosphorylation of p65 protein and induced ferroptosis through the Slug-SLC7A11 signaling pathway in GBM cells | |
OC | Eriodictyol | Phosphorylation | Nrf2 | Eriodictyol induces ferroptosis through downregulating Nrf2 phosphorylation,thereby decreasing protein levels of SLC7A11 and GPX4 | |
Thyroid cancers | RSL3 | Phosphorylation | mTOR | RSL3 activate ferroptosis through suppressing mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. | |
Pancreatic cancer | QD394 | Phosphorylation | STAT3 | QD394 induces ferroptosis through inhibiting STAT3 phosphorylation, thereby inhibiting GPX4 | |
ESCC | Allicin | Phosphorylation | AMPK | Allicin may induce ferritinophagy through increasing AMPK phosphorylation and decreasing mTOR |
