Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis
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ABSTRACT:
SUBMITTER: Do Q
PROVIDER: S-EPMC10131203 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.
2023-04-17 | GSE224249 | GEO
Project description:Differential Contributions of Distinct Free Radical Peroxidation Mechanisms to the Induction of Ferroptosis
| PRJNA930406 | ENA
Project description:To investigate how tumor heterogeneity involved in ferroptosis mediated by the physical microenvironment is a breakthrough in solving the therapeutic resistance of colorectal cancer (CRC). Based on the three-dimensional (3D) fibrin gel model, we identified four stages of epithelial-mesenchymal transition (EMT) in vitro that are synergistically regulated by mechanical cues and E-cadherin (ECAD) expression with varying degrees of resistance to ferroptosis. Mechanistically, we elucidated that 3D cells undergoing hybrid EMT fought ferroptosis via WNT/β-catenin-GPXs/ferritin signaling axis, while cells of a late-hybrid EMT state relied on adhesion tension forced mitohormesis to reach super defense against ferroptosis. This work deconstructed the distinct contributions of tumor heterogeneity to ferroptosis from an EMT perspective and uncovered the biomechanical weakness of therapeutic resistance. These findings, in conjunction with tumoroids, were expected to serve for future ferroptosis-based personalized diagnosis and treatment of CRC.
2025-04-23 | GSE240744 | GEO
Project description:Cancer represents a profound challenge to healthcare systems and individuals worldwide. The development of multiple drug resistance is a major problem in cancer therapy and can result in progression of the disease. In our previous studies, we developed small-molecule inhibitors targeting ubiquitin-specific peptidase 24 (USP24) to combat drug-resistant lung cancer. Recently, we found that the USP24 inhibitor NCI677397 induced ferroptosis, a type of programmed cell death, in drug-resistant cancer cells by increasing lipid reactive oxygen species (ROS) levels. In the present study, we investigated the molecular mechanisms and found that the targeting of USP24 by NCI677397 increased gene expression of most lipogenesis-related genes, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), and activated autophagy. In addition, the activity of several antioxidant enzymes, such as glutathione peroxidase 4 (GPX4) and dihydrofolate reductase (DHFR), was inhibited by NCI677397 treatment via an increase in protein degradation, thereby inducing lipid ROS production and lipid peroxidation. In summary, we demonstrated that NCI677397 induced a marked increase in lipid ROS levels, subsequently causing lipid peroxidation and leading to the ferroptotic death of drug-resistant cancer cells. Our study provides new insights into the clinical use of USP24 inhibitors as ferroptosis inducers (FINs) to block drug resistance during chemotherapy.
| S-EPMC11467797 | biostudies-literature
Project description:Photocyclization is demonstrated as a powerful tool for building complicated polycyclic molecules. And efficient photocyclization is competent as an artful strategy to develop photo-responsive smart materials. Herein, an efficient free radical-mediated photocyclization for triphenylphosphindole oxide (TPPIO) derivatives to generate tribenzophosphindole oxide (TBPIO) derivatives at ambient condition is reported. The reaction mechanism and substituent effect on photocyclization efficiency are thoroughly investigated. Additionally, photophysical and photochemical properties of TPPIO and TBPIO derivatives are measured for comparison and deeply deciphered by theoretical calculation. TPPIO derivatives own typical aggregation-induced emission feature but barely generate reactive oxygen species (ROS), while TBPIO derivatives experience aggregation-caused quenching but show efficient Type I ROS generation capacity. Further, in vitro experiments demonstrate that this photo-conversion can efficiently occur in situ in living cells to activate photodynamic therapy (PDT) effect to trigger lipid peroxidation with selective fluorescence "light up" in lipid droplet area under continuous irradiation. This work extends the optoelectronically and biologically interesting phosphindole oxide-containing π-conjugated systems through an efficient synthetic strategy, provides in-depth mechanistic descriptions in the aspects of reaction and property, and further presents their great potentials for photoactivated and self-reported PDT.
| S-EPMC10724397 | biostudies-literature
Project description:Ferroptosis is a type of regulated cell death characterized by lipid peroxidation and subsequent damage to the plasma membrane. Here, we report a ferroptosis resistance mechanism involving the upregulation of TXNDC12, a thioredoxin domain-containing protein located in the endoplasmic reticulum. The inducible expression of TXNDC12 during ferroptosis in leukemia cells is inhibited by the knockdown of the transcription factor ATF4, rather than NFE2L2. Mechanistically, TXNDC12 acts to inhibit lipid peroxidation without affecting iron accumulation during ferroptosis. When TXNDC12 is overexpressed, it restores the sensitivity of ATF4-knockdown cells to ferroptosis. Moreover, TXNDC12 plays a GPX4-independent role in inhibiting lipid peroxidation. The absence of TXNDC12 enhances the tumor-suppressive effects of ferroptosis induction in both cell culture and animal models. Collectively, these findings demonstrate an endoplasmic reticulum-based anti-ferroptosis pathway in cancer cells with potential translational applications.
| S-EPMC10690572 | biostudies-literature
Project description:Ferroptosis is primarily triggered by a failure of the glutathione (GSH)-glutathione peroxidase 4 (GPX4) reductive system and associated overwhelming lipid peroxidation, in which enzymes regulating polyunsaturated fatty acid (PUFA) metabolism, and in particular acyl-CoA synthetase long chain family member 4 (ACSL4), are central. Here, we found that exogenous oxygen radicals generated by photodynamic therapy (PDT) can directly peroxidize PUFAs and initiate lipid autoxidation, coinciding with cellular GSH depletion. Different from canonical ferroptosis induced by RSL3 or erastin, PDT-initiated lipid peroxidation and ferroptotis-like cell death is independent of lipoxygenase (ALOXs) and ACSL4. Especially, this form of cell death modality can be triggered in malignant cells insensitive to or acquired resistance to canonical ferroptosis inducers. We also observed a distinct iron metabolism pathway in this PDT-triggered cell death modality, in which cytosolic labile iron is decreased probably due to its relocation to mitochondria. Inhibition of the mitochondrial Ca2+ and Fe2+ uniporter (MCU) effectively prevented PDT-triggered lipid peroxidation and subsequent cell death. Therefore, we tentatively term this distinct ferroptosis-like cell death as liperoptosis. Moreover, using the clinically approved photosensitizer Verteporfin, PDT inhibited tumor growth through inducing prevailing ferroptosis-like cell death in a mouse xenograft model. With its site-specific advantages, these findings highlight the value of using PDT to trigger lipid peroxidation and ferroptosis-like cell death in vivo, and will benefit exploring the exact molecular mechanism of immunological effects of PDT in cancer treatment.
| S-EPMC8264218 | biostudies-literature
Project description:Although radiation is widely used to treat cancers, resistance mechanisms often develop and involve activation of DNA repair and inhibition of apoptosis. Therefore, compounds that sensitize cancer cells to radiation via alternative cell death pathways are valuable. We report here that ferroptosis, a form of nonapoptotic cell death driven by lipid peroxidation, is partly responsible for radiation-induced cancer cell death. Moreover, we found that small molecules activating ferroptosis through system xc- inhibition or GPX4 inhibition synergize with radiation to induce ferroptosis in several cancer types by enhancing cytoplasmic lipid peroxidation but not increasing DNA damage or caspase activation. Ferroptosis inducers synergized with cytoplasmic irradiation, but not nuclear irradiation. Finally, administration of ferroptosis inducers enhanced the antitumor effect of radiation in a murine xenograft model and in human patient-derived models of lung adenocarcinoma and glioma. These results suggest that ferroptosis inducers may be effective radiosensitizers that can expand the efficacy and range of indications for radiation therapy.
| S-EPMC7180072 | biostudies-literature
Project description:Ferroptosis is a regulated and non-apoptotic form of cell death mediated by iron-dependent peroxidation of polyunsaturated fatty acyl tails in phospholipids. Research of the past years has shed light on the occurrence of ferroptosis in organ injury and degenerative diseases of the brain, kidney, heart, and other tissues. Hence, ferroptosis inhibition may prove therapeutically beneficial to treat distinct diseases. In this study, we explored the ferroptosis-modulating activity of seratrodast, an inhibitor of thromboxane A2 (TXA2) receptor, which is approved in some countries for the treatment of asthma. Interestingly, seratrodast suppressed ferroptosis, but not apoptosis and necroptosis; thus, demonstrating selective anti-ferroptotic activity. While seratrodast itself does not inhibit lipid peroxidation, it exhibits potent radical-trapping antioxidant activity upon reduction to its corresponding hydroquinone form-analogously to ubiquinone and vitamin K. Importantly, seratrodast ameliorated the severity of renal ischemia-reperfusion injury in mice. Together, this study provides a drug repurposing case, where seratrodast-a marketed drug-can undergo fast-forward preclinical/clinical development for the inhibition of ferroptosis in distinct degenerative diseases.
| S-EPMC11584883 | biostudies-literature
Project description:Heparin, in a concentration-dependent manner, inhibited the generation of conjugated dienes and thiobarbituric acid-positive substances when incubated with Fe2+ and gamma-linolenic acid. In the conjugated diene assay, other glycosaminoglycans, on a molar basis calculated with respect to their respective hydrated disaccharide repeat units, were less effective than heparin. Heparin which had been re-N-sulphonated after removal of both N-sulphonates and O-sulphates, and heparin in which iduronate residues had been reduced to idose residues, were largely unaffected in their activity. Removal of both N-sulphonates and O-sulphates greatly reduced the effectiveness of the heparin. Analysis of the effects of heparin fragments generated by heparinase I treatment of heparin showed that depolymerization decreased the effectiveness of the heparin. It is possible that heparins and related strongly acidic polysaccharides may function as endogenous antioxidants, and that sequestration by them, or harmless oxidation by them, of ions such as Fe2+, contributes to their effectiveness.
| S-EPMC1132962 | biostudies-other