Regulation of Ferroptosis Pathway by Ubiquitination

Abstract

Ferroptosis is an iron-dependent form of programmed cell death, which plays crucial roles in tumorigenesis, ischemia–reperfusion injury and various human degenerative diseases. Ferroptosis is characterized by aberrant iron and lipid metabolisms. Mechanistically, excess of catalytic iron is capable of triggering lipid peroxidation followed by Fenton reaction to induce ferroptosis. The induction of ferroptosis can be inhibited by sufficient glutathione (GSH) synthesis via system Xc– transporter-mediated cystine uptake. Therefore, induction of ferroptosis by inhibition of cystine uptake or dampening of GSH synthesis has been considered as a novel strategy for cancer therapy, while reversal of ferroptotic effect is able to delay progression of diverse disorders, such as cardiopathy, steatohepatitis, and acute kidney injury. The ubiquitin (Ub)–proteasome pathway (UPP) dominates the majority of intracellular protein degradation by coupling Ub molecules to the lysine residues of protein substrate, which is subsequently recognized by the 26S proteasome for degradation. Ubiquitination is crucially involved in a variety of physiological and pathological processes. Modulation of ubiquitination system has been exhibited to be a potential strategy for cancer treatment. Currently, more and more emerged evidence has demonstrated that ubiquitous modification is involved in ferroptosis and dominates the vulnerability to ferroptosis in multiple types of cancer. In this review, we will summarize the current findings of ferroptosis surrounding the viewpoint of ubiquitination regulation. Furthermore, we also highlight the potential effect of ubiquitination modulation on the perspective of ferroptosis-targeted cancer therapy.

Iron supplementation enhances RSL3-induced ferroptosis to treat naïve and prevent castration-resistant prostate cancer

“…In addition, other pathways related to intracellular stress (i.e. autophagy and protein ubiquitination) have been detected by IPA analysis confirming the activation and presence of ferroptosis in DU145 cells treated with RSL3 + FAC [ 25 , 26 ] (Fig. S3 ).…”

Natural product piperlongumine inhibits proliferation of oral squamous carcinoma cells by inducing ferroptosis and inhibiting intracellular antioxidant capacity

“…Free Fe 2+ is transported into the cytoplasm by DMT1, participating in the formation of LIP, or being stored with FTH1 ( Figure 6 ). Subsequent LPO is provoked by excessive iron either by the iron-mediated Fenton reaction to produce ROS and capture hydrogen atoms from PL-PUFAs, or activating enzymes containing iron (for example, lipoxygenases) ( 26 , 27 ). As a radical-trapping antioxidant ( 28 ), Fer-1 is identified from screenings as potent ferroptosis inhibitors, and its activity lies in its capability to slow down the accumulation of lipid hydrogen peroxide ( 29 ).…”

Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma

“…By applying GO and KEGG, we confirmed that the gene that is co-expressed with ACSL4 is remarkably enriched in the pathway that is linked to protein ubiquitination. According to the findings of many research reports, the process of ubiquitination has a role in the modulation of the ferroptosis pathway (24). Recent research has shown that the protein BAP1 reduces the degree of histone 2A ubiquitination affinity to the promoters of the ferroptosis suppressor gene SLC7A11, which in turn suppresses the expression of SLC7A11 in a deubiquitinating-dependent way (25).…”