Ferroptosis and the bidirectional regulatory factor p53

Abstract

Ferroptosis is a type of regulated cell death characterized by iron-mediated lipid peroxidation, in contrast with apoptosis, autophagy, and necrosis. It can be triggered by many pathological processes, including cellular metabolism, tumors, neurodegenerative diseases, cardiovascular diseases, and ischemia–reperfusion injuries. In recent years, ferroptosis has been discovered to be associated with p53. P53 is a tumor suppressor protein with multiple and powerful functions in cell cycle arrest, senescence, cell death, repair of DNA damage, and mitophagy. Emerging evidence shows that ferroptosis plays a crucial role in tumor suppression by p53. P53 functions as a key bidirectional regulator of ferroptosis by adjusting metabolism of iron, lipids, glutathione peroxidase 4, reactive oxygen species, and amino acids via a canonical pathway. In addition, a noncanonical pathway of p53 that regulates ferroptosis has been discovered in recent years. The specific details require to be further clarified. These mechanisms provide new ideas for clinical applications, and translational studies of ferroptosis have been performed to treat various diseases.

Trappc1 intrinsically prevents ferroptosis of naive T cells to avoid spontaneous autoinflammatory disease in mice

“…In our study, we found that the P53 pathway was significantly increased in naive T cells of Trappc1 cKO mice. It is known that P53 could upreg-ulate the iron oxide reductase Steap3, which deoxidizes iron in Fe 3+ form to Fe 2+ [43]. Ultimately, DMT1-mediated release of Fe 2+ from endosomes into the cytoplasm leads to increased ROS production and increased lipid peroxidation [31,42].…”

“…In addition, P53 upregulates the iron oxide reductase Steap3, which reduces Fe 3+ form iron to Fe 2+ form iron. Ultimately, DMT1-mediated release of Fe 2+ from endosomes into the cytoplasm leads to increased ROS production and increased lipid peroxidation [31,43]. Thus, P53 is closely involved in the ferroptosis process.…”

SBFI26 induces triple‐negative breast cancer cells ferroptosis via lipid peroxidation

“…The first category of ferroptosis inducers triggers this process by depleting GSH; the second category directly targets GPX4 inactivation to induce ferroptosis; the third category induces ferroptosis by impairing both GPX4 and CoQ10 through the SQSme-mevalonate pathway, while the fourth category promotes lipid peroxidation by increasing LIP (Labile iron pool) or iron oxide. 38,41,42 Therefore, iron, lipids, and ROS constitute the fundamental components underlying ferroptosis. 60,61 Iron is necessary for lipid peroxide accumulation and ferroptosis.…”

“…ALOXs are non-heme iron-containing dioxygenases that catalyse the peroxidation and esterification of PUFAs, producing various biologically active lipid intermediates, including MDA. 49,65,68,69 P53 plays a crucial role in ferroptosis, 42,70,71 induces SAT1 expression, promoting ALOX15 function to enhance cell ferroptosis. 72,73 Wei Gu et al demonstrated that p53-ALOX12 can promote GSH-independent ferroptosis.…”

“…38 Extensive studies have established that ferroptosis plays a critical part in cancer progression, 39,40 and triggering ferroptosis could be a viable approach for anticancer treatments and mitigating chemotherapy resistance in cancerous cells. [41][42][43][44][45][46] Previous research has demonstrated that SBFI26 elicits intracellular apoptotic signals and induces apoptosis in PC3M cells by regulating the FABP5-VEGF-PPAR axis. 10,23 While previous studies have shown that SBFI26 can impede the proliferation of TNBC cells, its inhibitory effects on breast cancer have not yet been reported.…”