Environment & Health
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2026
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IF 8.8
Yueyue Mu,Jiawei Wu,Xiaomeng Ding,Yanting Pang,Yuna Cao,Jing Qu,Haopeng Zhang,Qing Liu,Ting Zhang
Indium tin oxide (ITO) particles, widely utilized in electronics and energy technologies, pose significant pulmonary risks due to occupational exposure during manufacturing. While emerging evidence links ITO to severe lung pathologies, critical gaps persist in understanding size-dependent effects and molecular mechanisms. This study systematically investigates the size-dependent effects of nanoscale ITO (N-ITO) and submicron-scale ITO (U-ITO) on pulmonary toxicity, focusing on ferroptosis as a key mechanism. In vivo, repeated oropharyngeal exposure of mice to ITO (3.6 and 36 mg/kg) induced dose-dependent lung inflammation and ferroptosis, marked by lipid peroxidation, Fe2+ accumulation, and dysregulation of Gpx4 and Scl7a11 proteins, with pulmonary macrophages identified as primary targets. In vitro, THP-1 macrophages exposed to 6.25–25 μg/mL ITO exhibited size-dependent cytotoxicity, inflammation, and ferroptotic hallmarks. Mechanistically, ITO-triggered ferroptosis promoted HMGB1 secretion and nuclear translocation, which activated the RAGE/p38MAPK pathway, amplifying inflammatory responses. Notably, N-ITO induced stronger ferroptosis and inflammation than U-ITO, correlating with enhanced macrophage uptake due to its nanoscale dimensions. Integrating these findings, we propose an Adverse Outcome Pathway (AOP) framework for ITO-induced lung injury, which cellular uptake may serve as the molecular initiating event and link ferroptosis-driven high mobility group protein B1 (HMGB1) release, RAGE/p38MAPK activation, and chronic inflammation to adverse pulmonary outcomes. This study underscores the necessity of size-specific occupational exposure limits for ITO nanoparticles and provides a mechanistic foundation for risk assessment and management strategies in occupational settings.
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FOOD RESEARCH INTERNATIONAL
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2026
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IF 8.8
Yueqin Qiu,Shilong Liu,Xinmiao Liao,Wenjing Wang,Jiaxi Tang,Li Wang,Xuefen Yang,Zongyong Jiang
Geniposide alleviated intestinal barrier dysfunction. • Geniposide increased Prevotella copri abundance to alleviate intestinal injury. • Geniposide inhibited diquat-induced intestinal ferroptosis in vivo and in vitro . • Geniposide regulated TRPV4/GPX4-mediated ferroptosis to alleviated intestinal injury. Early weaning disrupts intestinal antioxidant capacity and barrier integrity in human infants and young animals. Geniposide, an iridoid glycoside, exhibits anti-inflammatory and antioxidant activities. However, the mechanism by which geniposide ameliorates weaning-associated intestinal oxidative injury remains to be elucidated. Therefore, this study aimed to investigate whether and how geniposide attenuates intestinal injury, using diquat (DQ)-challenged weaned piglets, mice, and IPEC-J2 cells as experimental models. The results showed that geniposide supplementation significantly alleviated DQ-induced growth inhibition by increasing ADG and ADFI in the piglets. Additionally, geniposide significantly alleviated DQ-induced intestinal barrier damage, as evidenced by increased gene and protein expression of occludin and claudin-1 and decreased intestinal permeability in the ileum. Moreover, geniposide significantly attenuated DQ-induced oxidative stress, as shown by reduced levels of MDA, ROS, and 4-HNE, along with increased activities of T-AOC, GSH-Px, and T-SOD, as well as upregulated protein abundance of NRF2 and GCLM. Microbiome analysis showed that geniposide significantly increased Prevotella copri abundance in the ileum of DQ-challenged piglets. Prevotella copri supplementation alleviated DQ-induced intestinal injury in mice. Transcriptomic and non-targeted metabolomic analyses revealed that geniposide inhibited the DQ-induced ferroptosis signaling pathway. Additionally, geniposide significantly alleviated the DQ-induced the increases in the levels of MDA and Fe 2+ , and restored expression of the anti-ferroptotic proteins GPX4, SLC7A11, and FTL. Mechanistically, geniposide inhibited DQ-induced intestinal ferroptosis through modulation of the TRPV4/GPX4 pathway and increasing Prevotella copri abundance. Collectively, this study revealed that geniposide alleviated DQ-induced intestinal injury by modulating the TRPV4/GPX4-mediated ferroptosis pathway and increasing Prevotella copri abundance, suggesting its potential as a therapeutic agent against weaning-associated intestinal oxidative damage. Download: Download high-res image (117KB) Download: Download full-size image
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Pharmaceuticals
·
2026
·Vol. 19
·期 9
·1386
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IF 5.7
Yajun Zhou,Bangjian Liu,Hui Wang,Li Cao
Introduction: Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder involving ROS and ferroptosis. MXene, a 2D material, functions as both a drug carrier and ROS scavenger. Butylphthalide (NBP), a neuroprotective agent, suffers from poor aqueous solubility and bioavailability. This study synthesized Ti2C@BSA-NBP, a novel MXene nanocomposite, to enhance NBP delivery and therapeutic efficacy for AD.Materials and Methods: Ti2C@BSA-NBP was synthesized via self-assembly and amidation reaction, and characterized by multiple techniques. In vitro, ROS-scavenging capacity, mitochondrial function, and ferroptosis markers were assessed in H2O2-injured cells. In vivo efficacy was evaluated in an AD mouse model via behavioral, histopathological, and biochemical analyses. Results: The nanocomposite exhibited robust ROS-scavenging activity in vitro, significantly attenuating ROS, restoring mitochondrial function, and reversing ferroptosis markers. In vivo, Ti2C@BSA-NBP ameliorated learning/memory deficits, partially repaired neuronal morphology, and suppressed neuroinflammation. Mechanistically, it downregulated ACSL4 and Aβ overexpression while restoring GPX4 inhibition.Discussion: Ti2C@BSA-NBP exerts synergistic neuroprotection through MXene-mediated ROS clearance and NBP-mediated multi-target regulation, counteracting oxidative stress, ferroptosis, and neuroinflammation.Conclusions: Ti2C@BSA-NBP is a promising multifunctional nanoplatform integrating antioxidant activity, enhanced drug delivery, and ferroptosis modulation for AD therapy.
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Acta Biomaterialia
·
2023
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IF 9.7
Shuting Zheng,Honglei Hu,Meirong Hou,Kai Zhu,Zede Wu,Li Qi,Hui Xia,Guoqiang Liu,Yunyan Ren,Yikai Xu,Chenggong Yan,Bingxia Zhao
Although radiotherapeutic efficiency has been revealed to be positively correlated with ferroptosis , the neutral/alkaline cytoplasm pH value of tumor cells remains an intrinsic challenge for efficient Fenton/Fenton-like reaction-based ferroptosis induction. Herein, PEGylated hollow mesoporous organosilica nanotheranostics (HMON) [email protected] 2 nanoparticles (HGMP NPs) were designed as a ferroptosis inducer, which could specifically release Mn 2+ in tumor cells to activate the Fenton-like reaction for ferroptosis induction. Proton pump inhibitors (PPIs) were synchronously administered for cytoplasm pH level regulation by inhibiting V-H + -ATPases activity, enhancing Fenton-like reaction-based ferroptosis induction. Moreover, reactive oxygen species production was facilitated via the glucose oxidase triggered cascade catalytic reaction by utilizing intracellular β-D-glucose for H 2 O 2 self-supply and generation of additional cytoplasm H + . The PPI enhanced ferroptosis inducing nanosystem effectively inhibited tumor growth both in vitro and in vivo for tumor-specific ferroptosis induction and radiotherapy sensitization , suggesting that PPI administration could be an efficient adjuvant to reinforce Fenton/Fenton-like reaction-based ferroptosis induction for radiosensitization. Statement of significance The cytoplasm pH value of tumor cells is typically neutral to alkaline, which is higher than that of the Fenton/Fenton-like reaction desired acidic environments, hindering its efficiency. In this study, PEGylated hollow mesoporous organosilica nanotheranostics (HMON) [email protected] 2 nanoparticles were synthesized as a ferroptosis inducer, which could specifically release Mn 2+ via depleting glutathione and then activate the Fenton-like reaction in the tumor microenvironment. The glucose oxidase was applied for H 2 O 2 self-supply and addition of cytoplasm H + to further boost the Fenton-like reaction. We found that proton pump inhibitors (PPIs) increased intracellular acidification by inhibiting the activity of V-H + -ATPases to enhance the Fenton reaction-based ferroptosis induction, suggesting PPIs administration could be a feasible strategy to reinforce ferroptosis induction for radiosensitization.
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ENVIRONMENTAL POLLUTION
·
2023
·
IF 8.9
Dongxu Wang,Kai Yin,Yue Zhang,Hongmin Lu,Lulu Hou,Hongjing Zhao,Mingwei Xing
Endemic fluorosis (EF) has been listed as one of the serious public health problems in many countries. Long-term exposure to high fluoride can lead to severe neuropathological damage to the brain. Although long-term research has revealed the mechanism of some brain inflammation caused by excessive fluoride, the role of intercellular interactions, especially immune cells, in brain damage is still unclear. Fluoride can induce ferroptosis and inflammation in the brain in our study. A co-culture system of neutrophil extranets and primary neuronal cells showed that fluoride can aggravate neuronal cell inflammation by causing neutrophil extranets (NETs). In terms of the mechanism of action, we found that fluoride leads to the opening of calcium ion channels by causing neutrophil calcium imbalance, which in turn leads to the opening of L-type calcium ion channels (LTCC). Extracellular free iron enters the cell from the open LTCC, leading to neutrophil ferroptosis, which releases NETs. Blocking LTCC (nifedipine) rescued neutrophil ferroptosis and reduced the generation of NETs. Inhibition of ferroptosis (Fer-1) did not block cellular calcium imbalance. In summary, our study explores the role of NETs in fluoride-induced brain inflammation and suggests that blocking calcium channels may be one of the possibilities to rescue fluoride-induced ferroptosis.
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高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2023
·
IF 5.8
Ziwei Liang,Yuhui Wang,Jiapu Wang,Tao Xu,Shilong Ma,Qi Liu,Liqin Zhao,Yan Wei,Xiaojie Lian,Di Huang
Ferroptosis is a novel form of regulated cell death induced by iron-dependent lipid peroxidation imbalance. It has emerged as a promising antitumor therapeutic strategy in recent years. In this work, we successfully synthesized a complex magnetic nanocube Fe 3 O 4 modified with PEI and HA by the thermal decomposition method. While loading a ferroptosis inducer RSL3 inhibited cancer cells through the ferroptosis signal transduction pathway. The drug delivery system could actively target tumor cells through an external magnetic field and HA-CD44 binding. Zeta potential analysis showed that Fe 3 O 4 [email protected] nanoparticles were more stable and uniformly dispersed in tumor acidic environment. Moreover, cellular experiments demonstrated that Fe 3 O 4 [email protected] nanoparticles could significantly inhibit the proliferation of hepatoma cells without a cytotoxic effect on normal hepatic cells. In addition, Fe 3 O 4 [email protected] played a vital role in ferroptosis by accelerating ROS production. The expression of ferroptosis-related genes Lactoferrin, FACL 4, GPX 4 and Ferritin was significantly suppressed with increasing treatment of Fe 3 O 4 [email protected] nanocubes. Therefore, this ferroptosis nanomaterial has great potential in Hepatocellular carcinoma (HCC) therapy.
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高影响因子
Materials Today Bio
·
2023
·
IF 8.2
Fangying Yu,Xuwei Shang,Zixu Wang,Yun Zhu,Simin Chen,Hong Yuan,Fuqiang Hu
Ferroptosis as promising antitumor therapy strategy could be comprised by intracellular antioxidants, especially GSH and thioredoxin (Trx). They are both cofactors of Gpx4, the enzyme catalyzing the production of lipid peroxides to relieve oxidative stress, which drives the acquired ferroptosis resistance in tumors. Herein, the NADPH-consuming micelles are specially designed, which could collaborate with the ROS generating photodynamics therapy (PDT) by depleting intracellular GSH and Trx under hypoxia condition, resulting in ruined redox homeostasis and the final cascade amplified ferroptosis. The tailored micelle was briefly prepared by conjugating hypoxia-sensitive segment p-nitrobenzyl chloroformate (PNZ-Cl) to the hydrophilic chitosan (CS), the resulting micelle was further modified with photosensitizer Ce6 via PEG linkage. When receiving laser irradiation, the photosensitizer would generate ROS and consume oxygen in the meanwhile. The resulting anabatic hypoxia in turns promote the NTR-catalyzed electron-accepting response of micelles, with evidently enhanced NADPH consumption and ultimately ruined redox homeostasis, contributing to cascade amplified ferroptosis with robust ROS. Most importantly, the accompanied immunogenic cell death (ICD) and releasing danger-associated molecular patterns (DAMPs) could boost dendritic cells (DCs) maturation and the subsequent T-cell-mediated profound immune response. Collectively, the work excavates the other biochemical reaction during the hypoxia-sensitive process of C–N–Ce6 by diminishing intracellular GSH and Trx, providing a candidate of ferroptosis inducers against solid tumors.
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Acta Biomaterialia
·
2023
·
IF 9.7
Yuan Chen,Zhuo Yao,Peilian Liu,Qida Hu,Yong Huang,Li Ping,Fu Zhang,Honglin Tang,Tao Wan,Yuan Ping,Bowen Li
Chemotherapeutics have been recommended as the standard protocol for inoperable patients with triple-negative breast cancer (TNBC) at advanced stage, yet limited success has been achieved in prolonging survival rates by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Ferroptosis has become a powerful modality of no-apoptotic cell death, which can effectively evade chemo-resistance in apoptotic pathways. Herein, we propose an active-targeting small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and GPX4 inhibitor (RSL3) to overcome the chemo-resistance from traditional apoptotic pathways. In this nano-prodrug, the disulfide linkage not only serves as a GSH-responsive trigger, but also exhibits a stable self-assembly behavior that forms nanoparticle . Interestingly, the RSL3 can be loaded during this self-assembly process that forms a three-components nano-prodrug. In tumor environment, the high GSH level can disassemble the nano-prodrug to trigger the release of the parent drug, which can improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis. In different TNBC mice models, the nano-prodrug is encapsulated into RGD-modified phospholipid micelles (DSPE-PEG2000-RGD) and exhibits high anti-tumor and anti-metastasis efficacy, especially in orthotopic models. The application of ferroptosis to assist the enhancement of chemotherapeutics may serve as a promising strategy for TNBC treatment. Statement of significance Chemotherapeutics have been recommended as the standard of care for palliative and adjuvant treatment in patients with triple-negative breast cancer (TNBC), yet limited success has been achieved in prolonging the overall survival of patients by this monotherapy. A major reason for this failure is the chemo-resistance from traditional apoptotic pathways resulting in poor therapeutic effect. Thus, the co-delivery of the apoptosis and ferroptosis drug may overcome or evade the resistance in chemotherapy-induced apoptotic pathways and provide a promising strategy to combat TNBC. In this work, we developed a small-molecular self-assembly nano-prodrug for co-delivery of chemotherapeutics (CPT), Ferrocene (Fc) and ferroptosis resistance inhibitor (RSL3), which could overcome the chemo-resistance and improve the therapeutic effect by synergistic effects of ferroptosis and apoptosis.
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Food & Function
·
2023
·
IF 6.1
Haixia Che,Jie Yi,Xiaoting Zhao,Hong Yu,Xianyao Wang,Rui Zhang,Xin Li,Jia Fu,Qian Li
As a common plant-derived dietary flavonoid, rutin receives the widespread attention because of its good antioxidant bioactivities. Protein kinase Cα (PKCα) is a serine/threonine kinase that is involved in uncountable cellular processes, among which ferroptosis, a novel form of cell death, is triggered by lipid peroxidation and has been reported to associate with pulmonary arterial hypertension (PAH). But it is still not well appreciated how rutin inhibits ferroptosis in PAH and what function of PKCα plays in this process. In this study, we firstly observed whether rutin could prevent PAH by attenuating ferroptosis with PAH animal model and pulmonary artery smooth muscle cells (PASMCs) under hypoxia. Mitochondrial metabolomics and network pharmacology were employed to clarify the metabolic alteration and screen target proteins, results showed PKCα was a vital node in rutin regulating mitochondrial metabolism related to ferroptosis in PAH. Based on molecular docking and multispectral analysis, we found rutin could directly interact with PKCα through hydrogen bonds, which could induce static quenching, and then influence the secondary structure of PKCα. In conclusion, these findings mainly point to a novel mechanism that rutin protect PAH rat by modifying the structure, altering activity of PKCα, and then suppressing ferroptosis. This work was great helpful to reveal that the interaction behaviours between small molecules and bio-macromolecules are the critical point to develop the natural biological active ingredients and give an insight into the potential applications of flavonoid in health and disease.
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ACS Nano
·
2023
·
IF 17.1
Qiqi Zhang,Xuan Wang,Yuanyuan Zhao,Zhuo Cheng,De Fang,Yingqi Liu,Gan Tian,Menghuan Li,Zhong Luo
Low-dose radiotherapy (LDR) has shown significant implications for inflaming the immunosuppressive tumor microenvironment (TME). Surprisingly, we identify that FABP-dependent lipid droplet biogenesis in tumor cells is a key determinant of LDR-evoked cytotoxic and immunostimulatory effects and developed a nanointegrated strategy to promote the antitumor efficacy of LDR through cooperative ferroptosis immunotherapy. Specifically, TCPP-TK-PEG-PAMAM-FA, a nanoscale multicomponent functional polymer with self-assembly capability, was synthesized for cooperatively entrapping hafnium ions (Hf4+) and HIF-1α-inhibiting siRNAs (siHIF-1α). The TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α nanoassemblies are specifically taken in by folate receptor-overexpressing tumor cells and activated by the elevated cellular ROS stress. siHIF-1α could readily inhibit the FABP3/7 expression in tumor cells via HIF-1α-FABP3/7 signaling and abolish lipid droplet biogenesis for enhancing the peroxidation susceptibility of membrane lipids, which synergizes with the elevated ROS stress in the context of Hf4+-enhanced radiation exposure and evokes pronounced ferroptotic damage in vital membrane structures. Interestingly, TCPP@Hf-TK-PEG-PAMAM-FA@siHIF-1α-enhanced ferroptotic biomembrane damage also facilitates the exposure of tumor-associated antigens (TAAs) to promote post-LDR immunotherapeutic effects, leading to robust tumor regression in vivo. This study offers a nanointegrative approach to boost the antitumor effects of LDR through the utilization of tumor-intrinsic lipid metabolism.
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Ke Xue,Yongfei Zhao,Saidong Sun,Yuanhang Li,Jiankang Liang,Zhengjian Qi
Severe ferroptosis is a non-apoptotic iron-dependent cell death pathway, and extreme hypoxia and anomalous iron metabolism in tumors critically suppress the efficacy of ferroptosis therapy. Overcoming tumor hypoxia while facilitating ferroptosis is an extremely challenging task. Herein, the photosensitizer named BOTTQ with specific targeting of lipid droplet (LD) was synthesized by increasing the tail chain length of triphenylamine. The addition of alkoxy chains optimized the molecular structure and fostered inter-system crossing and type I reactive oxygen species (ROS) generation. Besides, BOTTQ yielded large amounts of type I ROS under light excitation oxidize efficiently polyunsaturated fatty acids in lipid monolayer of LD and contribute to the formation of ferroptosis substrate. Meanwhile, the generation of type I ROS accelerated the Fenton reaction, thus effectively boosting the occurrences of ferroptosis. Furthermore, the successful encapsulation of BOTTQ into DSPE-PEG-MAL material not only elevates the stable type of nanoparticle colloids, but the MAL moiety can deplete the functional thiols of glutathione in a mild environment, which leads to glutathione failure and facilitates ferroptosis. Thus tumor-specific ferroptosis-inducing strategy offers a universally applicable therapy with the capacity to enhance type I ROS production and effectively contain tumorigenesis.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2022
·
IF 8.101
Pingcui Xu,Bingfeng Lin,Xuehui Deng,Kai Huang,Yan Zhang,Nani Wang
Ferroptosis plays an essential role in the pathology of osteoporosis . This study investigated whether vitamin D receptor (VDR) activation could protect against age-related osteoporosis through an anti-ferroptosis mechanism. d -galactose (D-gal)-induced mice and VDR-knockout mice were used in the in-vivo study. The VDR activator (1,25(OH) 2 D 3 ) attenuated senescence and ferroptosis in the D-gal-induced bone, as illustrated by downregulated senescence-associated secretory phenotype genes, improved mitochondrial morphology, elevated glutathione , and decreased lipid peroxidation markers (malondialdehyde and 4-hydroxynonenal). The pre-osteoblast MC3T3-E1 cells and primary rat osteoblasts were applied in the in-vitro studies. 1,25(OH) 2 D 3 or ferroptosis inhibitor (ferrostatin-1) treatment downregulated the cellular senescence markers in D-gal-induced osteoblasts. Mechanistically, 1,25(OH) 2 D 3 activated the VDR and its downstream nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) signaling pathway , resulting in the downregulation of lipid peroxidation. Nrf2 knockdown or addition of GPX4 inhibitor (RSL-3) blocked the protective effect of 1,25(OH) 2 D 3 against D-gal-induced ferroptosis and senescence. VDR knockdown impeded the 1,25(OH) 2 D 3 -induced activation of Nrf2/GPX4 pathway in osteoblasts. Proteomics and immunofluorescence analysis confirmed that ferroptosis and suppression of the Nrf2/GPX4 pathway occurred in VDR-knockout mice. Our data demonstrated that ferroptosis played an essential role in age-related osteoporosis. The VDR activation attenuated osteoblast ferroptosis via stimulating the Nrf2/GPX4 signaling pathway.
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