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.
Highlights
All living organisms have been refined by the natural selection during the evolution
Since ubiquitination has been shown to largely participate in amino acid metabolism and autophagy regulation (Kwon and Ciechanover, 2017; Harper et al, 2018; Senft et al, 2018), we propose that ubiquitination is potentially closely related to the ferroptosis process
Emerging evidence has pointed out the potential role of ubiquitination in ferroptosis, the details of the mechanism remain to be elucidated
Summary
All living organisms have been refined by the natural selection during the evolution. It has been reported that p53 inhibits cystine uptake and sensitizes cells to ferroptosis by repressing the expression of SLC7A11 (Jiang et al, 2015), uncovering a novel role of p53 in ferroptosis. It has been showed that IR promotes ferroptosis in cancer cells (Lang et al, 2019), which is associated with elevation of ACSL4 expression, resulting in amplified lipid peroxidation (Lei et al, 2020).
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