The effect of ferroptosis - related proteins and histone deacetylases1 on neoadjuvant chemotherapy in breast cancer.

Ferroptosis may improve the efficacy of tumor treatment, according to recent evidences. This study is to explore value of histone deacetylases 1 (HDAC1), ATP binding cassette subfamily B member 1 and ferroptosis-related proteins as potential predictive biomarkers. Eighty-two women who received neoadjuvant chemotherapy (NAC) confirmed breast cancer was included. Immunohistochemistry staining of HDAC1, ATP binding cassette subfamily B member 1 and ferroptosis-related proteins was performed in core needle biopsy and tumor resection tissue. Univariate and multivariate logistic regression were conducted to explore the potential biomarkers for breast cancer undergoing NAC. There was a weak positive correlation of HDAC1 level before and after NAC with imaging outcome (R = 0.390, P < .001). The expression of HDAC1 and glutathione peroxidase 4 before NAC was an independent predictor of imaging efficacy (OR = 7.633, CI 1.831-31.821, P < .001; OR = 0.700, CI 0.505-0.971, P < .05, respectively). HDAC1 and Glutathione peroxidase 4 may act as a new predictive biomarker for NAC in breast cancer. And personalized treatment can be provided based on them.

Ferroptosis: mechanisms and implications for cancer development and therapy response.

As cancer cells develop resistance to apoptosis, non-apoptotic cell death modalities, such as ferroptosis, have emerged as promising strategies to combat therapy-resistant cancers. Cells that develop resistance to conventional therapies or metastatic cancer cells have been shown to have increased sensitivity to ferroptosis. Therefore, targeting the regulatory elements of ferroptosis in cancer could offer novel therapeutic opportunities. In this review, we first provide an overview of the known ferroptosis regulatory networks and discuss recent findings on how they contribute to cancer plasticity. We then expand into the critical role of selenium metabolism in regulating ferroptosis. Finally, we highlight specific cases where induction of ferroptosis could be used to sensitize cancer cells to this form of cell death.

Resveratrol inhibits ferroptosis via activating NRF2/GPX4 pathway in mice with spinal cord injury.

Ferroptosis is a newly defined form of cell death involved in neurologic disease. Resveratrol is a non-flavonoid polyphenolic compound with anti-inflammatory and antioxidant properties, but its potential therapeutic mechanism in spinal cord injury (SCI) remains unknown. Therefore, this study evaluates the mechanism by which resveratrol promotes neurological and motor function recovery in mice with SCI. The motor function of mice was evaluated using the Basso Mouse Scale score and footprint test. The effect of resveratrol on the neuronal cell state was observed using NeuN, fluoro-Jade C, and Nissl staining. The expression of iron content in injured segments was observed using Perls blue and Diaminobenzidine staining. The effect of resveratrol on the levels of malondialdehyde, glutathione, Fe2+ , and glutathione peroxidase 4 enzyme activity was also investigated. The mitochondrial ultrastructures of injured segment cells were observed using transmission electron microscope, while the protein levels of ferroptosis-related targets were detected using Western blot. Our findings show that resveratrol improves motor function after SCI and has certain neuroprotective effects; in ferroptosis-related studies, resveratrol inhibited the expression of ferroptosis-related proteins and ions. Resveratrol improved changes in mitochondrial morphology. Mechanistically, the Nrf2 inhibitor ML385 reversed the inhibitory effect of resveratrol on ferroptosis-related genes, indicating that resveratrol inhibits ferroptosis through the Nrf2/GPX4 pathway. Our findings elucidate that resveratrol promotes functional recovery, inhibits ferroptosis post-SCI, and provides an experimental basis for subsequent clinical translational research. Our study shows that resveratrol inhibits the production of lipid peroxide and the accumulation of iron by activating Nrf2/GPX4 signaling pathway, thereby inhibiting neuronal ferroptosis. At the same time, it can promote the recovery of motor function of mice.

Potent nanoreactor-mediated ferroptosis-based strategy for the reversal of cancer chemoresistance to Sorafenib.

The drug resistance of cancer cells is related to a variety of mechanisms, among which the destruction of redox homeostasis is one of the key factors. Ferroptosis, an intracellular iron-dependent form of cell death, is related to the production of oxidative stress. The accumulation of lipid peroxidation (LPO) during ferroptosis disrupts intracellular redox homeostasis, thereby affecting the sensitivity of tumor cells to drugs. In this work, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein and inactivated glutathione peroxidase 4 (GPX4) to reverse the chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO, but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG + Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'. The study proposed the mechanism and feasibility of ferroptosis to reverse drug resistance, providing a promising strategy for chemo-resistant cancer treatment. STATEMENT OF SIGNIFICANCE: Herein, we proposed a ferroptosis strategy based on LPO accumulation, reduced glutathione generation via inhibition of SLC3A2 protein, and inactivated glutathione peroxidase 4 (GPX4) to reverse chemoresistance of cancer cells. The Fenton reaction based on the ferroptosis-inducing nanoreactors (Au/Fe-GA/Sorafenib@PEG) not only generated hydroxyl radicals (·OH) under laser irradiation to realize the accumulation of LPO but also depleted GSH to increase the accumulation of LPO. Meanwhile, the cystine uptake of cells was inhibited by Sorafenib, resulting in reduced GSH synthesis and inactivated GPX4. In vitro and in vivo experiments demonstrated AFG/SFB@PEG + Laser group could inactivate GPX4 and the enhanced ferroptosis can reverse chemo-resistance caused by continuous upregulation of GPX4 levels in cells through 'self-rescue'.

Protective Effects and Mechanisms of Recombinant Human Glutathione Peroxidase 4 on Isoproterenol-Induced Myocardial Ischemia Injury.

Ischemic heart disease (IHD) is a cardiovascular disease with high fatality rate, and its pathogenesis is closely related to oxidative stress. Reactive oxygen species (ROS) in oxidative stress can lead to myocardial ischemia (MI) injury in many ways. Therefore, the application of antioxidants may be an effective way to prevent IHD. In recent years, glutathione peroxidase 4 (GPx4) has received increasing attention due to its antioxidant effect. In a previous study, we used the new chimeric tRNAUTuT6 to express highly active recombinant human GPx4 (rhGPx4) in amber-less Escherichia coli. In this study, we established an isoproterenol- (ISO-) induced MI injury model in rats and an in vitro model to research the protective effect and mechanism of rhGPx4 on MI injury. The results showed that rhGPx4 could reduce the area of myocardial infarction and ameliorate the pathological injury of heart tissue, significantly reduce ISO-induced abnormalities on electrocardiogram (ECG) and cardiac serum biomarkers, protect mitochondrial function, and attenuate cardiac oxidative stress injury. In an in vitro model, the results also confirmed that rhGPx4 could inhibit ISO-induced oxidative stress injury and cardiomyocyte apoptosis. The mechanism of action of rhGPx4 involves not only the inhibition of lipid peroxidation by eliminating ROS but also keeping a normal level of endogenous antioxidant enzymes by eliminating ROS, thereby preventing oxidative stress injury in cardiomyocytes. Additionally, rhGPx4 could inhibit cardiomyocyte apoptosis through a mitochondria-dependent pathway. In short, rhGPx4, a recombinant antioxidant enzyme, can play an important role in the prevention of IHD and may have great potential for application.

Neuroprotective role of glutathione peroxidase 4 in experimental subarachnoid hemorrhage models.

BACKGROUND AND PURPOSE: Early brain injury is an essential pathological process after subarachnoid hemorrhage (SAH), with many cell death modalities. Ferroptosis is a newly discovered regulated cell death caused by the iron-dependent accumulation of lipid peroxidation, which can be prevented by glutathione peroxidase 4 (GPX4). Our study aimed to investigate the role of GPX4 in neuronal cell death after experimental SAH. METHODS: In vivo experimental SAH was induced by injecting autologous arterial blood into the prechiasmatic cistern in male Sprague-Dawley rats. Meanwhile, the in vitro SAH model was performed with primary rat cortical neurons cultured in medium containing hemoglobin (Hb). Adenovirus was used to overexpress GPX4 before experimental SAH. GPX4 expression was detected by western blot and immunofluorescence experiments. Malondialdehyde (MDA) was measured to evaluate the level of lipid peroxidation. Nissl staining was employed to assess cell death in vivo, whereas lactate dehydrogenase (LDH) release was used to evaluate cell damage in vitro. The brain water content and neurological deficits were evaluated to determine brain injury. RESULTS: Endogenous GPX4 was mainly expressed in neurons, and its expression decreased at 24 h after experimental SAH. Overexpression of GPX4 significantly reduced lipid peroxidation and cell death in the experimental SAH models both in vivo and in vitro. Moreover, overexpression of GPX4 ameliorated brain edema and neurological deficits at 24 h after SAH. CONCLUSIONS: The decrease of GPX4 expression potentially plays an important role in ferroptosis during early brain injury after SAH. Overexpression of GPX4 has a neuroprotective effect after SAH.