Peroxide Accumulation Research Articles

NIR-responsive copper nanoliposome composites for cascaded ferrotherapy via ferroptosis actived ICD and IFN-γ released

Metallic biomaterials activate tumor ferroptosis by increasing oxidative stress, but their efficacy is severely limited in tumor microenvironment. Although interferon gamma (IFN-γ) can promote tumor ferroptosis sensitivity by inhibiting the antioxidant system and promoting lipid accumulation, this effect limited by the lack of IFN-γ accumulation in tumors. Herein, we report a near-infrared (NIR)-responsive HCuS nanocomposite (HCuS-PE@TSL-tlyp-1) that can stimulate immunogenic cell death (ICD)-mediated IFN-γ secretion through exogenous oxidative stress, thereby achieving cascaded ferrotherapy by mutually reinforcing ferroptosis and systemic immunity. Upon laser irradiation, the dissolution of the thermal coating, and the introduction of Cu ions and piperazine-erastin (PE) simultaneously induce oxidative stress by reactive oxygen species (ROS)/lipid peroxide (LPO) accumulation and deplete cystine-glutamate transporter (xCT)/GSH. The onset of oxidative stress-mediated ferroptosis is thus achieved, and ICD is triggered, significantly promoting cytotoxic T-cell (CTL) infiltration for IFN-γ secretion. Furthermore, IFN-γ induces immunogenic tumor ferroptosis by inhibiting xCT-antioxidant pathways and enhancing the ACSL4-fatty acid recruitment pathway, which further promotes sensitivity to ferroptosis in cells. These HCuS nanocomposites combined with aPD-L1 effectively in inhibiting tumor metastasis and recurrence. Importantly, these cascade ferrotherapy results broadens the application of HCuS biomaterials.

FSP1-mediated ferroptosis in cancer: from mechanisms to therapeutic applications.

Ferroptosis is a new discovered regulated cell death triggered by the ferrous ion (Fe2+)-dependent accumulation of lipid peroxides associated with cancer and many other diseases. The mechanism of ferroptosis includes oxidation systems (such as enzymatic oxidation and free radical oxidation) and antioxidant systems (such as GSH/GPX4, CoQ10/FSP1, BH4/GCH1 and VKORC1L1/VK). Among them, ferroptosis suppressor protein 1 (FSP1), as a crucial regulatory factor in the antioxidant system, has shown a crucial role in ferroptosis. FSP1 has been well validated to ferroptosis in three ways, and a variety of intracellular factors and drug molecules can alleviate ferroptosis via FSP1, which has been demonstrated to alter the sensitivity and effectiveness of cancer therapies, including chemotherapy, radiotherapy, targeted therapy and immunotherapy. This review aims to provide important frameworks that, bring the regulation of FSP1 mediated ferroptosis into cancer therapies on the basis of existing studies.

Exogenous methyl jasmonate enhanced kenaf (Hibiscus cannabinus) tolerance against lead(Pb) toxicity by improving antioxidant capacity and osmoregulators.

In this study, the effects of exogenous methyl jasmonate (MeJA) on metal uptake and its ability to attenuate metal toxicity in kenaf plants under Pb stress were investigated. The experiment was conducted with five different MeJA concentrations (0, 40, 80, 160, and 320 μM) as a foilar application to kenaf plants exposed to 200 μM Pb stress. The results revealed that pretreatmen of MeJA significantly increased plant dry weight, plant height, and root architecture at all concentrations tested, with the most significant increase at 320 μM. Foliar application of MeJA at 160 μM and 320 μM increased the Pb concentrations in leaves and stems as well as the translocation factor (TF) from root to leaf. However, the bioaccumulation factor in the shoot initially decreased and then increased with increasing MeJA concentration. By increasing enzymatic (SOD, POD, and CAT) and non-enzymatic (AsA and non-protein thiols) antioxidants, MeJA pretreatment decreased lipid peroxidation, O2- and H2O2 accumulation and recovered photosynthetic pigment content under Pb stress. Increased osmolytes (proline, sugar, and starch) and protein content after MeJA pretreatment under Pb stress restore cellular homeostasis and improved kenaf tolerance. Our results suggest that MeJA pretreatment modifies the antioxidant machinery of kenaf and inhibits stress-related processes that cause lipid peroxidation, hence enhancing plant tolerance to Pb stress.

Comparative and interactive response of salicylic acid, 24–epibrassinolide or sodium nitroprusside against cadmium stress in Linum usitatissimum

AbstractConcerns regarding the effects of heavy metals (HMs) on agricultural productivity have grown over time. Because HM stress disrupts a number of the plants' physiological-biochemical and metabolic processes, it severely limits production. Phytohormones can effectively improve plants resistance to HM stress. This work was done to examine the comparative effectiveness of salicylic acid (SA), 24–epibrassinolide (EBL) and sodium nitroprusside (SNP) on photosynthetic attributes, growth, & antioxidant enzymes activity in Linum usitatissimum cv. RLC–6 (flax) subjected to cadmium (Cd) stress during vegetative growth stages. Cd considerably decreases the length, biomass, leaf diameter, chlorophyll content, and photosynthetic traits; and further triggered ROS and MDA content in plant. Moreover, exogenous application of SA, EBL and SNP individually and in combination improved the antioxidant enzymatic machinery by increasing the levels of superoxide dismutase (SOD), peroxidase (POX), and catalase (CAT) and decrease the superoxide, hydrogen peroxide, scavenges ROS and MDA accumulation. Furthermore, submission of phytohormones also caused proline to accumulate and the activities of carbonic anhydrase (CA) and nitrate reductase (NR) to be activated which were impaired due to Cd stress. Among the phytohormones, the most effective method for dropping the damaging impacts of Cd and promoting plant growth and development was EBL. However, combined application of all three phytohormones (SA + EBL + SNP) proved to be the best. Thus, it can be concluded that, these augmented activity of antioxidants and proline elicited by application of phytohormones, would have continued to be able to give Linum usitatissimum exposed to Cd stress resistance.

Mechanisms of UHP alleviates waterlogging-induced damage in ginger (Zingiber officinale)

In recent years, global climate anomalies and frequent flooding disasters have led to large-scale reduction and even crop failures of ginger production, severely restricting the normal production of ginger. However, the mitigation mechanism under waterlogging stress has not been reported in ginger. In order to investigate the physiological mechanism of the mitigation of waterlogging stress in ginger, the experiment was set up by soil application of urea peroxide(UHP) of different concentration (T1: 0 g·L−1; T2: 40 g·L−1; T3: 80 g·L−1; T4:120 g·L−1) after 2 d of waterlogging. The results showed that waterlogging stress significantly increased the accumulation of ROS and membrane lipid peroxidation in ginger roots and leaves. The chlorophyll content and photosynthetic performance were significantly decreased, and the net photosynthetic rate (Pn), Fv/Fm and ΦPSII of T1 were reduced by 123.5%, 18.8%, and 43.4% compared with that of CK, respectively. Exogenous application of UHP significantly improved the growth of ginger seedlings after waterlogging stress. UHP promoted the rapid recovery of ginger seedlings under waterlogging stress by restoring the normal physiological activity of the root system, and the root activity of T3 was significantly increased by 118.9% compared with that of T1. UHP protected the cellular structure of ginger leaves and improved the H2O-CO2 exchange capacity, and the Pn and stomatal conductance (Gs) of T3 were significantly increased by 961% and 21.8% compared with that of T1, respectively. In addition, the Fv/Fm and ΦPSII of T3 were increased by 20.6% and 48.2% compared with that of T1, respectively. UHP also significantly increased the activity of antioxidant enzymes, and the levels of ROS and membrane damage were significantly reduced.

Diselenide-Containing Polymer Based on New Antitumor Mechanism as Efficient GSH Depletion Agent for Ferroptosis Therapy.

Glutathione (GSH) depletion-induced ferroptosis has emerged as a promising treatment for malignant cancer. It works by inactivating glutathione peroxidase 4 (GPX4) and facilitating lipid peroxidation. However, effectively delivering inducers and depleting intracellular GSH remains challenging due to the short half-lives and high hydrophobicity of small-molecule ferroptosis inducers. These inducers often require additional carriers. Herein, diselenide-containing polymers can consume GSH to induce ferroptosis for pancreatic cancer therapy. The diselenide bonds are controllably built into the backbone of the polycarbonate with a targeting peptide CRGD (Cys-Arg-Gly-Asp), which allows for self-assembly into stable nanoparticles (denoted CRNSe) for self-delivery. Significantly, at a concentration of 12 µg mL-1, CRNSe binds to the active site cysteine of GSH resulting in a thorough depletion of GSH. In contrast, the disulfide-containing analog only causes a slight decrease in GSH level. Moreover, the depletion of GSH inactivates GPX4, ultimately inducing ferroptosis due to the accumulation of lipid peroxide in BxPC-3 cells. Both in vitro and in vivo studies have demonstrated that CRNSe exhibits potent tumor suppressive ability with few side effects on normal tissue. This study validates the anti-tumor mechanism of diselenide-containing polymers in addition to apoptosis and also provides a new strategy for inherently inducing ferroptosis in cancer therapy.

Abstract LB299: Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer

Abstract Dihydrouridine is a universally conserved tRNA modification installed by enzymes that are important for human health. High expression of dihydrouridine synthase 2 (DUS2) predicts poor patient outcomes in lung adenocarcinoma (LUAD) for reasons that are not yet clear. Here, we show in human cells and mouse xenografts that DUS2 suppresses ferroptosis, a metal-dependent non-apoptotic form of cell death that is emerging as a therapeutic target in lung cancer. Elevated DUS2 correlates with resistance to ferroptosis inducers and loss of DUS2 causes increased sensitivity with concomitant accumulation of toxic lipid peroxides. Mechanistically, DUS2 is required to maintain tRNA CysGCA levels, supporting translation of cysteine-rich proteins including metallothioneins, key regulators of metal and redox homeostasis Notably, DUS2 KO cells cannot sustain normal levels of metallothioneins, a class of very cysteine rich proteins that serve as key regulators of both metal and redox homeostasis. Accordingly, DUS2 knockout cells are more susceptible to zinc intoxication and have lower levels of reduced glutathione, which partially explains their sensitivity to ferroptosis. Our findings demonstrate that DUS2 is required to support tRNACys levels and fend off ferroptosis in lung cancer cells. This highlights that individual tRNA substrates can play an outsized role in the biological functions of tRNA modifying enzymes, and demonstrates the therapeutic potential of targeting DUS2 in cancer. Citation Format: Austin Draycott, Matthew C. Wang, Diana Martínez Saucedo, Luisa Escobar-Hoyos, Wendy Gilbert. Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB299.

Surufatinib combined with photodynamic therapy induces ferroptosis to inhibit cholangiocarcinoma in vitro and in tumor models.

The curative effect of single therapy for advanced cholangiocarcinoma (CCA) is poor, thus investigating combined treatment strategies holds promise for improving prognosis. Surufatinib (SUR) is a novel multikinase inhibitor that has been confirmed to prolong survival of patients with advanced CCA. Photodynamic therapy (PDT) can also ablate advanced CCA and relieve biliary obstruction. In this study, we explored the anti-CCA effect of SUR combined with PDT, and explored the underlying mechanism. We found that SUR could effectively inhibit the abilities of proliferation, migration and metastasis in CCA cells (HUCCT-1, RBE). The ability of SUR to inhibit CCA was also confirmed by the HUCCT-1 cell xenograft model in Balb/c nude mice and CCA patient-derived organoids. SUR combined with PDT can significantly enhance the inhibitory effect on CCA, and can be alleviated by two ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). By detecting the level of reactive oxygen species, lipid peroxides, malondialdehyde and glutathione, we further confirmed that SUR combined with PDT can inhibit CCA cells by inducing ferroptosis. Glutathione peroxidase 4 (GPX4) belongs to the glutathione peroxidase family and is mainly responsible for the metabolism of intracellular hydrogen peroxide. GPX4 inhibits ferroptosis by reducing cytotoxic lipid peroxides (L-OOH) to the corresponding alcohols (L-OH). Acyl-CoA synthetase long-chain family member 4 (ACSL4) is a member of the long-chain fatty acid coenzyme a synthetase family and is mainly involved in the biosynthesis and catabolism of fatty acids. ACSL4 induces ferroptosis by promoting the accumulation of lipid peroxides. Both SUR and PDT can induce ferroptosis by promoting ACSL4 and inhibiting GPX4. The regulation effect is found to be more significant in combined treatment group. In conclusion, SUR combined with PDT exerted an anti-CCA effect by inducing ferroptosis. Combination therapy provides a new idea for the clinical treatment of CCA.

Bcl-xL regulates radiation-induced ferroptosis through chaperone-mediated autophagy of GPX4 in tumor cells

ObjectiveTo investigate the role and the molecular mechanisms of apoptotic signaling in ferroptosis to regulate tumor radiosensitivity. MethodsReactive oxygen species (ROS) and lipid peroxide levels were detected in Mouse embryonic fibroblasts(MEFs) with Bcl-xL or Mcl-1 deficiency induced by erastin. Colony formation, ROS, lipid peroxidation and the transcription/translation levels of PTGS2 were measured in Bcl-xL knockdown tumor cells induced by 5 ​Gy γ-rays or co-treated with ferrostatin-1 (Ferr-1). The protein levels of LPCAT3, ACSL4 and PEBP1 in Bcl-xL knockout MEF cells were evaluated in Bcl-xL knockout MEF cells post-radiation. Moreover, the interaction of heat shock protein 90 (HSP90) with Bcl-xL, GPX4, or LAMP2A was detected by protein mass spectrometry and immunoprecipitation assays. ResultsManipulating Bcl-xL levels facilitated radiation-induced ferroptosis by augmenting the enzymatic oxidation of polyunsaturated fatty acids (PUFAs) and enhancing chaperone-mediated autophagy (CMA) of glutathione peroxidase 4 (GPX4) (MEF cell line: t=4.540, P＜0.01; A549 ​cell line: t=56.16, P＜0.0001; t=4.885, P＜0.01; HCT116 ​cell line: t=14.75, P＜0.01; t=7.363, P＜0.05). Downregulating Bcl-xL expression promoted the activity of acyl-CoA synthetase long-chain family member 4 (ACSL4), thus increasing the enzymatic oxidation of PUFAs (t=4.258, P＜0.01). Moreover, depletion of Bcl-xL expedited the CMA process targeting GPX4 by facilitating the association of GPX4 with heat shock protein 90 (HSP90) and LAMP2A following radiation exposure. Subsequent degradation of GPX4 led to the accumulation of lipid peroxides, ultimately triggering ferroptosis. ConclusionsOur study provides initial insights into the regulatory role of Bcl-xL in ferroptosis and underscores the potential of targeting Bcl-xL as a promising therapeutic strategy for cancer by modulating both apoptotic and ferroptotic pathways.

LncRNA RGMB-AS1 inhibits HMOX1 ubiquitination and NAA10 activation to induce ferroptosis in non-small cell lung cancer

Ferroptosis, an iron-dependent regulated cell death caused by excessive lipid peroxide accumulation, has emerged as a promising therapeutic target in various cancers, including non-small cell lung cancer (NSCLC). In this study, we identified the long non-coding RNA RGMB-AS1 as a key regulator of ferroptosis in NSCLC. Mechanistically, RGMB-AS1 interacted with heme oxygenase 1 (HMOX1) and prevented its ubiquitination by the E3 ligase TRC8, leading to increased HMOX1 stability and enhanced ferroptosis. Additionally, RGMB-AS1 bound to the 82–87 amino acid region of N-alpha-acetyltransferase 10 (NAA10), stimulating its acetyltransferase activity and promoting the conversion of acetyl-CoA to HMG-CoA, further contributing to ferroptosis. The RGMB-AS1-HMOX1 and RGMB-AS1-NAA10 axes synergistically inhibited NSCLC growth both in vitro and in vivo. Clinically, low RGMB-AS1 expression was associated with advanced tumor stage and poor overall survival in NSCLC patients. Furthermore, adeno-associated virus-mediated RGMB-AS1 overexpression significantly suppressed tumor growth in mouse xenograft models. Our findings uncover a novel lncRNA-mediated regulatory mechanism of ferroptosis and highlight the potential of RGMB-AS1 as a prognostic biomarker and therapeutic target in NSCLC.

Oxaliplatin-Loaded Mil-100(Fe) for Chemotherapy-Ferroptosis Combined Therapy for Gastric Cancer.

Oxaliplatin (Oxa) is a commonly used chemotherapy drug in the treatment of gastric cancer, but its toxic side effects and drug resistance after long-term use have seriously limited its efficacy. Loading chemotherapy drugs with nanomaterials and delivering them to the tumor site are common ways to overcome the above problems. However, nanomaterials as carriers do not have therapeutic functions on their own, and the effect of single chemotherapy is relatively limited, so there is still room for progress in related research. Herein, we construct Oxa@Mil-100(Fe) nanocomposites by loading Oxa with a metal-organic framework (MOF) Mil-100(Fe) with high biocompatibility and a large specific surface area. The pore structure of Mil-100(Fe) is conducive to a large amount of Oxa loading with a drug-loading rate of up to 27.2%. Oxa@Mil-100(Fe) is responsive to the tumor microenvironment (TME) and can release Oxa and Fe3+ under external stimulation. On the one hand, Oxa can inhibit the synthesis of DNA and induce the apoptosis of gastric cancer cells. On the other hand, Fe3+ can clear overexpressed glutathione (GSH) in TME and be reduced to Fe2+, inhibiting the activity of glutathione peroxidase 4 (GPX4), leading to the accumulation of intracellular lipid peroxides (LPO), and at the same time releasing a large number of reactive oxygen species (ROS) through the Fenton reaction, inducing ferroptosis in gastric cancer cells. With the combination of apoptosis and ferroptosis, Oxa@Mil-100(Fe) shows a good therapeutic effect, and the killing effect on gastric cancer cells is obvious. In a nude mouse model of subcutaneous tumor transplantation, Oxa@Mil-100(Fe) shows a significant inhibitory effect on tumor growth, with an inhibition rate of nearly 60%. In addition to its excellent antitumor activity, Oxa@Mil-100(Fe) has no obvious toxic or side effects. This study provides a new idea and method for the combined treatment of gastric cancer.

Spatiotemporally-controlled supramolecular hybrid nanoassembly enabling ferroptosis-augmented photodynamic immunotherapy of cancer

Photodynamic therapy (PDT) not only directly eradicates tumor cells but also boosts immunogenicity, promoting antigen presentation and immune cell infiltration. However, the robust antioxidant defense mechanisms within tumor cells significantly weaken the efficacy of photodynamic immunotherapy. Herein, a supramolecular hybrid nanoassembly is constructed by exploring the synergistic effects of the photodynamic photosensitizer (pyropheophorbide a, PPa) and the ferroptosis inducer (erastin). The erastin-mediated inhibition of system Xc− significantly downregulates glutathione (GSH) expression, amplifying intracellular oxidative stress, leading to pronounced cell apoptosis, and promoting the release of damage-associated molecular patterns (DAMPs). Additionally, the precise cooperation of PPa and erastin enhances ferroptosis efficiency, exacerbating the accumulation of lipid peroxides (LPOs). Ultimately, LPOs serve as a “find me” signal, while DMAPs act as an “eat me” signal, collectively promoting dendritic cell maturation, enhancing infiltration of the cytotoxic T lymphocytes, and eliciting a robust immune response. This study opens new horizons for enhancing tumor immunotherapy through simultaneous ferroptosis-PDT.

Inhibition of Anaplastic Lymphoma Kinase Protects From Ischemic Stroke.

Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke.

ML162 derivatives incorporating a naphthoquinone unit as ferroptosis/apoptosis inducers: Design, synthesis, anti-cancer activity, and drug-resistance reversal evaluation

Activating apoptosis has long been viewed as an anti-cancer process, but recently increasing evidence has accumulated that induction of ferroptosis has emerged as a promising strategy for cancer therapeutics. Glutathione peroxidase 4 (GPX4) is one of the pivotal factors regulating ferroptosis that targeted inhibition or degradation of GPX4 could effectively trigger ferroptosis. In this study, a series of ML162-quinone conjugates were constructed by using pharmacophore hybridization and bioisosterism strategies, with the aim of obtaining more active anticancer agents via the ferroptosis and apoptosis dual cell death processes. Of these compounds, GIC-20 was identified as the most active one that exhibited promising anticancer activity both in vitro and in vivo via ferroptosis and apoptosis dual-targeting processes, without obvious toxicity compared with ML162. On one hand, GIC-20 could trigger ferroptosis in cells by inducing intracellular lipid peroxide and ROS accumulation, and destroying mitochondrial structure. In addition to GPX4 inhibition, GIC-20 can also trigger ferroptosis via proteasomal-mediated degradation of GPX4, suggesting GIC-20 may function as a molecule glue degrader. On the other hand, GIC-20 can also induce apoptosis via upregulating the level of apoptotic protein Bax and downregulating the level of anti-apoptotic protein Bcl-2 in HT1080 cells. Furthermore, GIC-20 also enhanced the sensitivity of resistant MIA-PaCa-2-AMG510R cells to AMG510, suggesting the great potential of GIC-20 in overcoming the acquired resistance of KRASG12C inhibitors. Overall, GIC-20 represents a novel dual ferroptosis/apoptosis inducer warranting further development for cancer therapeutics and overcoming drug resistance.

Vitamin D inhibits ferroptosis and mitigates the kidney injury of prediabetic mice by activating the Klotho/p53 signaling pathway.

Diabetic nephropathy (DN) is a serious public health problem worldwide, and ferroptosis is deeply involved in the pathogenesis of DN. Prediabetes is a critical period in the prevention and control of diabetes and its complications, in which kidney injury occurs. This study aimed to explore whether ferroptosis would induce kidney injury in prediabetic mice, and whether vitamin D (VD) supplementation is capable of preventing kidney injury by inhibiting ferroptosis, while discussing the potential mechanisms. High-fat diet (HFD) fed KKAy mice and high glucose (HG) treated HK-2 cells were used as experimental subjects in the current study. Our results revealed that serious injury and ferroptosis take place in the kidney tissue of prediabetic mice; furthermore, VD intervention significantly improved the kidney structure and function in prediabetic mice and inhibited ferroptosis, showing ameliorated iron deposition, enhanced antioxidant capability, reduced reactive oxygen species (ROS) and lipid peroxidation accumulation. Meanwhile, VD up-regulated Klotho, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, and down-regulated p53, transferrin receptor 1 (TFR1) and Acyl-Coenzyme A synthetase long-chain family member 4 (ACSL4) expression. Moreover, we demonstrated that HG-induced ferroptosis is antagonized by treatment of VD and knockdown of Klotho attenuates the protective effect of VD on ferroptosis in vitro. In conclusion, ferroptosis occurs in the kidney of prediabetic mice and VD owns a protective effect on prediabetic kidney injury, possibly by via the Klotho/p53 pathway, thus inhibiting hyperglycemia-induced ferroptosis.

Protective Role of Dioscin against Doxorubicin-Induced Chronic Cardiotoxicity: Insights from Nrf2-GPX4 Axis-Mediated Cardiac Ferroptosis.

Recent evidence suggests that ferroptosis, an iron-facilitated cell death with excessive lipid peroxidation, is a critical mechanism underlying doxorubicin (DOX)-induced cardiotoxicity (DIC). Although dioscin has been reported to improve acute DIC, direct evidence is lacking to clarify the role of dioscin in chronic DIC and its potential mechanism in cardiac ferroptosis. In this study, we used chronic DIC rat models and H9c2 cells to investigate the potential of dioscin to mitigate DIC by inhibiting ferroptosis. Our results suggest that dioscin significantly improves chronic DIC-induced cardiac dysfunction. Meanwhile, it significantly inhibited DOX-induced ferroptosis by reducing Fe2+ and lipid peroxidation accumulation, maintaining mitochondrial integrity, increasing glutathione peroxidase 4 (GPX4) expression, and decreasing acyl-CoA synthetase long-chain family 4 (ACSL4) expression. Through transcriptomic analysis and subsequent validation, we found that the anti-ferroptotic effects of dioscin are achieved by regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)/GPX4 axis and Nrf2 downstream iron metabolism genes. Dioscin further downregulates nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and upregulates expression of frataxin (FXN) and ATP-binding cassette B8 (ABCB8) to limit mitochondrial Fe2+ and lipid peroxide accumulation. However, Nrf2 inhibition diminishes the anti-ferroptotic effects of dioscin, leading to decreased GPX4 expression and increased lipid peroxidation. This study is a compelling demonstration that dioscin can effectively reduce DIC by inhibiting ferroptosis, which is dependent on the Nrf2/GPX4 pathway modulation.

Physiological responses, ion accumulation and yield performance of wheat (Triticum aestivum L.) to salt stress

Wheat is affected by various biotic and abiotic stresses, especially salinity, which reduces the growth and yield drastically. High salinity is a major constraint for wheat productivity in many countries, including Bangladesh. With this view, here, an experiment was conducted to observe genotypic differences in physiological, ion accumulation, agro-morphological and yield performance of wheat against different levels of salinity. Experimental variables consisted of five salt tolerant genotypes (G 20–2–2, G 20–1–2, G 13–2, G 22–2, G 9–2), one susceptible genotype (G 24–2) and one standard check variety (BARI ghom 25), which assigned to four levels of salinity with electrical conductivities control (0.3), 4, 8 and 12 dS m−1. Irrespective of genotypes, salinity stress significantly decreased the yield and yield attributes. Results of analyses based on salt tolerance indices of plant growth related and yield contributing parameters, ionic balance (Na+, K+ and Na+ /K+ ratio), and stress indicators such as chlorophyll content, photosynthetic rate (Pn), stomatal conductance (gs) and transpiration rate (Tr) revealed genotypes G 20–2–2, G 13–2 and G 20–1–2 as salt tolerant, genotype G 9–2 as moderately salt-tolerant and G 24–2 and G 22–2 as salt-sensitive genotypes. Additionally, lower accumulations of hydrogen peroxide and malondialdehyde, and higher activities of antioxidant enzymes in the salt-tolerant genotypes G 20–2–2 and G 13–2 than in the salt-sensitive genotype G 24–2 indicated reduced oxidative damage in genotypes G 20–2–2 and G 13–2 relative to that in genotype G 24–2. Collectively, our findings suggest that the optimum growth and yield of salt tolerant genotypes are associated with decreased Na+/K+ ratio, increased antioxidant enzymes activity and reduced oxidative stress.

FeP-Based Nanotheranostic Platform for Enhanced Phototherapy/Ferroptosis/Chemodynamic Therapy.

Ferroptosis is an iron-dependent and lipid peroxides (LPO)-overloaded programmed damage cell death, induced by glutathione (GSH) depletion and glutathione peroxide 4 (GPX4) inactivation. However, the inadequacy of endogenous iron and reactive oxygen species (ROS) restricts the efficacy of ferroptosis. To overcome this obstacle, a near-infrared photo-responsive FeP@PEG NPs is fabricated. Exogenous iron pool can enhance the effect of ferroptosis via the depletion of GSH and further regulate GPX4 inactivation. Generation of ·OH derived from the Fenton reaction is proved by increased accumulation of lipid peroxides. The heat generated by photothermal therapy and ROS generated by photodynamic therapy can enhance cell apoptosis under near-infrared (NIR-808nm) irradiation, as evidenced by mitochondrial dysfunction and further accumulation of lipid peroxide content. FeP@PEG NPs can significantly inhibit the growth of several types of cancer cells in vitro and in vivo, which is validated by theoretical and experimental results. Meanwhile, FeP@PEG NPs show excellent T2-weighted magnetic resonance imaging (MRI) property. In summary, the FeP-based nanotheranostic platform for enhanced phototherapy/ferroptosis/chemodynamic therapy provides a reliable opportunity for clinical cancer theranostics.

A carrier-free metal-phenolic network with enhanced ferroptosis-immunotherapy for overcoming tumor resistance and metastasis

The development of multidrug resistance (MDR) is the primary contributor to the failure of cancer treatment, ultimately leading to tumor recurrence and metastasis. Ferroptosis, an iron-dependent cell death form related to the accumulation of lipid peroxidation (LPO), has the potential to circumvent MDR. Furthermore, recent breakthroughs have confirmed that the inhibition of cyclooxygenase-2 (COX-2) not only facilitate LPO and ferroptosis, but also suppress the expression of p-glycoprotein. Therefore, the combination of immunogenic ferroptosis with COX-2 inhibitors may be an enticing approach for overcoming tumor resistance and metastasis. Herein, polyphenolic COX-2 inhibitors are first screened using molecular docking, enzyme-linked immunosorbent assay, and combination index analysis. Then, a carrier-free metal-phenolic networks are constructed based on the coordination between polyphenolic COX-2 inhibitors and Fe3+, and DOX and dopamine-modified hyaluronic acid are directly decorated using a one-pot process. The nanosystem can selectively inhibit the COX-2 pathway, thereby suppressing the expression of p-glycoprotein and enhancing Fe3+-induced ferroptosis; Additionally, the nanosystem demonstrates excellent photothermal performance, promoting ferroptosis and synergistically triggering strong immune responses against tumor metastasis. The RNA-seq analysis further confirmes the transcriptomic alterations in drug resistance and ferroptosis pathways induced by the nanosystem. Taken together, this study provides a promising strategy for efficient cancer treatment.

Dibutyl phthalate exposure induced mitochondria-dependent ferroptosis by enhancing VDAC2 in zebrafish ZF4 cells

Dibutyl phthalate (DBP) contamination has raised global concern for decades, while its health risk with toxic mechanisms requires further elaboration. This study used zebrafish ZF4 cells to investigate the toxicity of ferroptosis with underlying mechanisms in response to DBP exposure. Results showed that DBP induced ferroptosis, characterized by accumulation of ferrous iron, lipid peroxidation, and decrease of glutathione peroxidase 4 levels in a time-dependent manner, subsequently reduced cell viability. Transcriptome analysis revealed that voltage-dependent anion-selective channel (VDAC) in mitochondrial outer membrane was upregulated in ferroptosis signaling pathways. Protecting mitochondria with a VDAC2 inhibitor or siRNAs attenuated the accumulation of mitochondrial superoxide and lipid peroxides, the opening of mitochondrial permeability transition pore (mPTP), and the overload of iron levels, suggesting VDAC2 oligomerization mediated the influx of iron into mitochondria that is predominant and responsible for mitochondria-dependent ferroptosis under DBP exposure. Furthermore, the pivotal role of activating transcription factor 4 (ATF4) was identified in the transcriptional regulation of vdac2 by ChIP assay. And the intervention of atf4b inhibited DBP-induced VDAC2 upregulation and oligomerization. Taken together, this study reveals that ATF4-VDAC2 signaling pathway is involved in the DBP-induced ferroptosis in zebrafish ZF4 cells, contributing to the in-depth understanding of biotoxicity and the ecological risk assessment of phthalates.