Advanced Science
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2026
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IF 14.1
Wanbing Qin,Jiaqi Huang,Manting Zhang,Wanchun Yang,Mingwei Xu,Chi Jiang,Jiekai Li,Jinjuan Wen,Qibin Huang,Shiqi Wen,Weidong Wang,Junbing He,Qinghua Liu
Cisplatin‐induced acute kidney injury (CI‐AKI) is a frequent, dose‐dependent complication in patients receiving cisplatin chemotherapy, and effective targeted treatments remain unavailable. The development of targeted therapies for CI‐AKI may improve the efficacy of chemotherapy while mitigating renal toxicity. Given that ferroptosis is a key pathological mechanism in CI‐AKI, targeted drug delivery systems against this process represent a promising therapeutic strategy. Dipeptidase 1 (DPEP1) is highly expressed in renal proximal tubular brush borders and has been associated with ferroptosis regulation and tubular injury. In this study, mesoporous polydopamine nanoparticles (MPDA NPs) were engineered for renal‐targeted delivery of cilastatin sodium (CTT), a specific DPEP1 inhibitor, through L‐serine (L‐Ser) surface modification (CTT/MPDA@L‐Ser NPs). In vitro experiments demonstrated that CTT/MPDA@L‐Ser NPs inhibited the expression of DPEP1 to upregulate the expression of the ferroptosis‐suppressing protein glutathione peroxidase 4 (GPX4), thereby suppressing ferroptosis pathways. In AKI mice, CTT/MPDA@L‐Ser NPs exhibited selective renal accumulation, significantly ameliorating serum creatinine and blood urea nitrogen levels. Collectively, CTT/MPDA@L‐Ser NPs exhibited potent therapeutic efficacy against AKI, presenting a promising strategy for targeted AKI management. In this study, MPDA NPs were engineered to encapsulate CTT. To further increase renal accumulation of CTT, L‐serine was conjugated to the surface of the MPDA nanoparticles (CTT/MPDA@L‐Ser NPs). CTT/MPDA@L‐Ser NPs inhibit DPEP1 activity, thereby restoring ferroptosis defense mechanisms through upregulation of GPX4 and SLC7A11 expression, ultimately mitigating cisplatin‐induced AKI pathology.
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高影响因子
Redox Biology
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2026
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IF 16.2
Zhiying Yang,Rui Ma,Weili Wu,Ying Shi,You Chen,Xiaotong Luo,Kai Li,Liangcai Wu,Bo Wang,Boyu Zhang,Ping Yuan
The lack of effective therapeutic options available for microsatellite stable (MSS) colorectal cancer (CRC) remains a significant clinical challenge. Interestingly, chemotherapy-resistant cancer cells can be induced to undergo ferroptosis, prompting our investigation into RSL3, a potent ferroptosis inducer, in MSS CRC cells. Our findings revealed that while RSL3 suppressed the growth of MSS CRC cells, a subset displayed resistance. Single-cell sequencing uncovered an aberrant activation of hypoxia pathways in RSL3-resistant MSS CRC cells. Inhibiting HIF-1α, the key transcription factor driving hypoxia signaling, restored RSL3 sensitivity in these resistant cells; moreover, this sensitivity was attenuated upon HIF-1α overexpression. Chromatin immunoprecipitation assays further demonstrated that in RSL3-resistant cells, HIF-1α was enriched at the promoter of P4HA1, a gene implicated in ferroptosis resistance, thereby enhancing its expression. Additionally, in vivo experiments using syngeneic transplantation of CT26 cells in mice revealed that combining RSL3 with an HIF-1α inhibitor markedly enhanced tumor suppression and metastasis prevention, concomitant with increased intratumoral infiltration of CD8 + T cells and CD86 + macrophages. Notably, the combination enhanced the antitumor response of anti-PD1, a treatment otherwise ineffective on this tumor. These findings suggest that targeting HIF-1α represents a promising therapeutic strategy when used in conjunction with a ferroptosis inducer for the treatment of MSS CRC.
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PubMed
高影响因子
Materials Today Bio
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2026
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IF 11
Yihui Zhang,Yujun Mo,Bingbing Yan,Xiaoyi Wang,Ping Wu,YunGang Wu,Zhouguang Wang
Severe spinal cord injury (SCI) frequently causes persistent neurological deficits, and its repair is constrained by multiple pathological factors including deterioration of the microenvironment following secondary injury, massive neuronal loss, interruption of electrical signal conduction, and insufficient endogenous regenerative capacity. Although electroacupuncture (EA) participates in the rehabilitation of SCI by regulating inflammatory responses and promoting the secretion of neurotrophic factors, standalone EA therapy can hardly fully reverse oxidative stress, ferroptosis and neural circuit destruction following severe SCI. Accordingly, this study constructs a conductive anti-ferroptosis hydrogel system (HBP@BMSCs), which utilizes dopamine-grafted hyaluronic acid (HADA) as the bionic matrix, baicalin-polypyrrole (BA-PPy) as the functional component, and is loaded with bone marrow mesenchymal stem cells (BMSCs). This hydrogel system is combined with EA for the repair of severe SCI. The results demonstrate that the HBP hydrogel exhibits favorable cytocompatibility, which can support the survival of BMSCs and maintain their typical mesenchymal stem cell phenotype. In vitro experiments demonstrate that HBP hydrogel effectively alleviates TBHP-induced oxidative stress injury and Erastin-induced ferroptosis-related injury, and exerts a protective effect on BMSCs and PC12 cells. In vivo experiments further confirmed that the combination therapy of HBP@BMSCs with EA significantly downregulated the expression levels of 4HNE, COX2, NOX2, FTH, FTL and TFR after SCI, and restored the expression levels of XCT, GPX4, SOD1 and FPN, thereby alleviating ROS accumulation, lipid peroxidation, iron overload and ferroptosis. With the alleviation of oxidative stress and ferroptosis-related secondary damage, the combination therapy further downregulates the expression of Bax and C-caspase3, upregulates Bcl-2 levels, and significantly inhibits neuronal apoptosis. In addition, the BA-PPy conductive network can synergize with EA to enhance electrical stimulation conduction, upregulate NGF/NGFR and BDNF neurotrophic signaling pathways, and promote the neural lineage differentiation of BMSCs, axon regeneration, corticospinal tract (CST) remodeling, and the recovery of motor function. In conclusion, HBP@BMSCs combined with EA exerts multiple synergistic effects including microenvironment remodeling, anti-ferroptosis protection, stem cell delivery and electroactive neural regeneration, providing a comprehensive therapeutic strategy with translational potential for severe SCI repair. Scheme 1. Schematic diagram of the synthesis and synergistic EA treatment of HBP@BMSCs. Download: Download high-res image (284KB) Download: Download full-size image
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高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Xinrui Yan,Linfeng Ma,Jing Ren,Binyan Chen,Wenxuan Song,Yu Dong,Xiaojiao Li,Yingjie Guo
Valproic acid (VPA), a widely used antiepileptic drug, often induces hepatic steatosis during long-term treatment, though the underlying mechanisms remain incompletely understood. In our study, epileptic patients with abnormal liver function exhibited significantly elevated levels of homocysteine (Hcy) and glutamate (Glu) compared to those with normal liver function. Moreover, Hcy and Glu levels were positively correlated with markers of lipid accumulation and oxidative stress. Similar elevations in Hcy and Glu were observed in VPA-treated mice and hepatocyte models (HepG2, AML12), suggesting that disrupted Hcy/Glu homeostasis may be a hallmark of VPA-induced hepatic steatosis. Further in vitro experiments demonstrated that treatment with either Hcy or Glu not only increased lipid accumulation but also triggered ferroptosis, as indicated by Fe 2+ overload, suppression of the GSH-GPX4 axis, and ACSL4-mediated lipid peroxidation. These effects were attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1), confirming the contribution of ferroptosis to Hcy/Glu-induced hepatotoxicity. Additional investigations revealed that VPA promotes Hcy accumulation by downregulating its catabolic enzymes (MTR, CBS, CTH), while enhancing Glu accumulation through upregulation of its synthetic enzymes (ALDH4A1, GLS) and repression of the catabolic enzyme GLUL, both in vivo and in vitro . The alterations in MTR, CBS, ALDH4A1, and GLS levels were shown to depend on HDAC1, as demonstrated using HDAC1 knockdown and overexpression systems in HepG2 cells. In summary, VPA disrupts Hcy/Glu homeostasis via HDAC1, leading to ferroptosis and subsequent hepatic steatosis. These findings highlight the HDAC1-Hcy/Glu-ferroptosis axis as a promising therapeutic target for mitigating VPA-induced hepatotoxicity.
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高影响因子
Acta Pharmaceutica Sinica B
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2026
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IF 14.6
Ruizhe Xu,Xuejing Li,Xiaomin Su,Xifeng Qin,Ying He,Siyu Wang,Yue Liu,Jiayi Wu,Ting Wang,Mingyang Liu,Boshu Ouyang,Jia Li,Wuli Yang,Bo Zhang,Zhiqing Pang
The efficient targeted delivery and on-demand release of nanomedicines still present significant challenges in tumor therapy. In the present study, we developed a novel strategy of tumor ferroptosis therapy through the synergistic effect of nanomedicines (biomimetic liposomes) and a medical device (high-intensity focused ultrasound, HIFU). It was found that HIFU irradiation induced heightened expressions of CD44 and reactive oxygen species (ROS) in tumor cells by 1.43-fold and 2.64-fold, respectively. This allowed the gambogic acid-loaded, platelet-mimicking liposomes (PLip) to more precisely target the tumor cells through the interaction of CD44 and P-selectin on the PLip and subsequently ROS-responsively release the drug from PLip, thus effectively killing tumor cells. Crucially, gambogic acid also significantly enhanced ROS production, leading to lipid peroxidation and augmented ferroptosis induced by HIFU. In summary, HIFU demonstrates immense potential in synergizing with nanomedicines to combat tumors.
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高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2026
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IF 3.6
Yilin Wang,Shenglai Zhou,Xiaopeng Yu,Junfeng Cui,Tengfei Wu
Emerging evidence suggests that triggering ferroptosis could be a promising approach for combating breast cancer. Here, we investigated the role of aurantio-obtusin (AO), a key bioactive compound sourced from Cassiae semen, in the treatment of breast cancer. Cell viability and death were determined via a CCK-8 assay and propidium iodide (PI) staining. Ferroptosis was determined by the levels of Fe2+, lipid ROS, and GSH. Autophagy was assessed by immunofluorescence staining. An MDA-MB-231 cell transplantation tumor model was established in vivo. AO inhibited breast cancer cell growth in a concentration-dependent manner while promoting cell death. Ferroptotic changes, including blockage of the GSH–GPX4 antioxidation system, massive iron release, and lipid ROS accumulation, were evident in AO-treated breast cancer cells. Antioxidant N -acetylcysteine (NAC) treatment markedly restored GSH content and suppressed lipid ROS overproduction to relieve AO-triggered ferroptosis. The introduction of the iron scavenger deferoxamine or the ferroptosis inhibitor ferrostatin-1 weakened AO-induced ferroptosis in breast cancer cells. Moreover, AO treatment promoted autophagosome formation in breast cancer cells via the mTOR-ULK1 pathway. AO-induced autophagy and ferroptosis were both reversed by Atg7 knockdown or mTOR activator MHY1485 treatment. Network pharmacology and molecular docking investigations suggested that EGFR was a potential target of AO in breast cancer and that its protein expression was suppressed by AO. Selective EGFR inhibitor gefitinib exacerbated AO-mediated ferroptosis and autophagy, while genetic overexpression of EGFR completely reversed these AO-mediated phenotypes. In vivo assays confirmed the antitumor effects of AO. Our study revealed that AO facilitated autophagy-dependent ferroptosis in breast cancer cells through the downregulation of EGFR. This work provides a new perspective on the antitumor activity of AO, which is valuable for further investigations of the practical application of AO in breast cancer.
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高影响因子
ADVANCED MATERIALS
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2026
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IF 29.1
Zekai Zhuang,Renlu Han,Yafei Hou,Qixiong Zhang,Jiancheng Yu,Na Li,Geng Wang,Jie Fu,Zhaozheng Deng,Hongwei Song,Yifei Qi,Keqi Tang
Ultrasound (US) induced piezoelectric catalytic therapy is an emerging cancer treatment method. However, the development and optimization of piezoelectric catalyst remain the major challenge. Herein, we have converted the classical dielectric material CaCu 3 Ti 4 O 12 (CCTO) into an efficient piezoelectric material through oxygen vacancy (V O ) engineering, enabling piezoelectric catalytic-driven cascade tumor therapy. The introduction of V O results in strong polarization and a robust piezoelectric coefficient. Density functional theory (DFT) calculations reveal that V O acts as an electron trap to suppress the recombination of electron and hole, enhancing the catalytic efficiency. The piezoelectric effect can “open” the cell membrane, facilitating the materials influx and triggering reactive oxygen species (ROS) storm. Meanwhile, the cavitation effect of US and tumor cell over-expressed glutathione (GSH) accelerate Cu and Ca release, causing intracellular ions overload. ROS and Ca ions damage mitochondria to evoke apoptosis, which accordingly shuts down the Cu + outflow pathway and expedites cuproptosis. Moreover, ROS and GSH depletion triggers ferroptosis. This process establishes a positive feedback loop mechanism. Transcriptome sequencing confirms the activation of cell death-related pathways. This study represents the first paradigm to create piezoelectricity through V O in CCTO for tumor therapy, advancing the applications of quadruple perovskites in tumor treatment.
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高影响因子
Journal of Environmental Sciences
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2026
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IF 6.5
Hongjing Zhao,Jiayin Yue,Yushan Song,Zizheng Wang,Mingwei Xing,Yu Wang
Arsenic induces time-dependent ferroptosis in zebrafish embryonic (ZF4) cells. • Ncoa4-mediated ferritinophagy plays a critical role in arsenic-induced ferroptosis. • Early arsenic exposure suppresses Ncoa4 and accumulates FTH1, delaying ferroptosis. • Late-phase arsenic activates Ncoa4, promoting ferritin degradation and iron release. • Melatonin alleviates arsenic-induced ferroptosis via Nrf2-dependent antioxidant pathway. Arsenic (As) is a widely distributed toxic pollutant worldwide, posing severe threats to the health of animals and plants. Transcriptomic analysis of zebrafish embryonic cells (ZF4) revealed that exposure to trivalent arsenic (arsenite, As 3+ ) significantly altered levels of FTH1 (ferritin heavy chain 1) and Ncoa4 (nuclear receptor coactivator 4), and was closely associated with the proteasome pathway. Based on these findings, we further investigated the mechanisms underlying As-induced cell death and potential intervention strategies. The results showed that As induced autophagic cell death. Ferroptosis occurred as a late event and was regulated by Ncoa4-mediated ferritinophagy: during the early stage of As exposure, FTH1 accumulated independently of Ncoa4 changes, likely as a protective iron-sequestering response; whereas in the late stage, Ncoa4 activation promoted ferritin degradation and iron release, ultimately triggering ferroptosis. Moreover, melatonin (1 mmol/L) significantly alleviated As-induced ferroptosis by strengthening cellular antioxidant capacity through activation of the Nrf2 signaling pathway. Overall, this study reveals a critical regulatory role of Ncoa4 in As-induced ferroptosis and provides experimental evidence supporting targeted intervention strategies for arsenic poisoning. Download: Download high-res image (284KB) Download: Download full-size image
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高影响因子
Food Bioscience
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2026
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IF 6.2
Jiawen Lu,Ying Yang,Xingtao Zhou,Qiang Yu,Jianhua Xie,Yi Chen
Acrylamide (AA) and 5-hydroxymethylfurfural (HMF) are common food processing hazards frequently co-existing in thermally processed foods. Although both hazards have been reported to induce oxidative stress and cytotoxicity, their co-exposure effects on intestinal epithelial cells remain unclear. Here, we investigated the co-exposure effects and mechanisms of AA and HMF in intestinal epithelial IEC-6 cells. Co-exposure significantly reduced cell viability, disrupted redox homeostasis, and impaired mitochondrial function, as evidenced by glutathione depletion, increased lipid peroxidation, and mitochondrial membrane potential loss. Multiple lines of evidence supported the involvement of ferroptosis, including glutathione peroxidase 4 (GPX4) downregulation, intracellular iron accumulation, lipid reactive oxygen species (ROS) generation, and the protective effect of ferrostatin-1. Transcriptomic analysis further provided supportive evidence for ferroptosis-related pathways, which was further supported by decreased SLC7A11 expression. In parallel, alterations in autophagy-related markers and lysosomal function were observed, and chloroquine partially attenuated cellular injury, suggesting that impaired autophagic degradation may contribute to the cellular response to AA and HMF exposure. In addition, co-exposure induced nuclear accumulation of Nrf2 together with increased HO-1 expression, indicating activation of an adaptive antioxidant response to oxidative stress. Collectively, AA and HMF co-exposure induced intestinal epithelial injury associated with ferroptosis, accompanied by autophagy-lysosome dysfunction and activation of the Nrf2/HO-1 signaling. These findings improve our understanding of the cellular mechanisms underlying AA and HMF co-exposure in intestinal epithelial cells.
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高影响因子
Science China-Chemistry
·
2025
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IF 9.7
Gao Ji,Lu Song-Bo,Wang Fangliang,Zha Menglei,Li Kai
Ferroptosis, a form of unique cell death characterized by iron and iron-dependent accumulation of lipid peroxidation, has attracted increasing attention for cancer therapy. However, the antitumor efficacies of current small-molecule ferroptosis inducers are always not potent enough, and there is a debate over whether ferroptosis induces immunogenic or nonimmunogenic cell death. Guided by the pharmacophore concept, we rationally design a rhodanine-based small-molecule ferroptosis inducer, which can target the endoplasmic reticulum (ER) as a pivotal center for lipid metabolism. Metabolic and proteomic analyses suggest that the inducer causes dysregulation of cellular lipid metabolism, which can contribute to cell ferroptosis. In vivo results indicate that it triggers immunogenic cell death and activates the immune response to suppress tumor growth, accompanied by reversing the immunosuppressive tumor microenvironment and enhancing immunological memory. Furthermore, this inducer has an intrinsic photodynamic character that can further promote therapeutic efficacy with a single treatment. Specifically, the populations of CD8 + and CD4 + T cells in the spleen of tumor-bearing mice show a 3.2-fold and 2.6-fold increase upon treatment, respectively. Overall, this innovative approach has the potential to enhance antitumor therapies by exploiting the benefits of ferroptosis and immune activation, providing a working principle for further investigation of ferroptosis-based therapeutic strategies.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Haoyu Yang,Xin Chen,Siqi Huang,Hongfang Dai,Zuowei Xiao,Jialong Fan,Honggang Zhang,Ke Du,Yan Qin
Ferroptosis and cuproptosis are two important new forms of ion-dependent cell death, whose processes can be inhibited by high levels of glutathione (GSH) within cells. Therefore, reducing GSH levels is a key strategy for inducing ferroptosis and cuproptosis. Herein, we successfully developed a curcumin (Cur) derivative, bisdemethylcurcumin (bm-Cur), as a novel GSH depletor that simultaneously induces ferroptosis and cuproptosis in hepatocellular carcinoma (HCC). The unique polyphenolic hydroxy structure and double α, β-unsaturated ketone structure of bm-Cur confers its potent GSH scavenging ability, which can effectively deplete GSH by simultaneously inhibiting GSH synthesis and directly consuming GSH levels, ultimately inducing ferroptosis and cuproptosis. Notably, bm-Cur can target mitochondria, induce mitochondrial lipid peroxidation and mitochondrial damage, thereby promoting ferroptosis and cuproptosis-mediated cell death, which demonstrates potential for anti-HCC activity in vitro and in vivo . Moreover, bm-Cur exhibited very low cytotoxicity, excellent biosafety and biocompatibility. In conclusion, this study suggests that bm-Cur may be a novel ferroptosis and cuproptosis activator with significant development potential for further application.
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高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2025
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IF 3.9
Yang Feng,Senyue Liu,Xiaoli Huang,Yi Geng,Chengyan Mou,Han Zhao,Jian Zhou,Qiang Li,Yongqiang Deng
Overwintering syndrome (OWS) causes massive mortality in grass carp ( Ctenopharyngodon idella ) during early spring, yet its pathogenesis beyond the "low-temperature–pathogen" paradigm remains unclear. This study investigates the cascade mechanism through integrated multi-omics analyses on gill tissues of healthy and OWS-affected grass carp. Gill histopathology revealed progressive necrotizing inflammation in OWS-affected grass carp. Transcriptomics identified 962 differentially expressed genes, highlighting upregulation of cytokine signaling, porphyrin metabolism, and ferroptosis alongside downregulation of adrenergic pathways. Ferroptosis was confirmed through the suppression of glutathione peroxidase 4 (GPX4) and the accumulation of iron in necrotic lamellae. Mucous cell depletion and eosinophil disintegration compromised the mucosal barriers of the gills. Metagenomic analysis first revealed a state of microbial dysbiosis, marked by bacterial dominance comprising 92.21% of the community, along with an enrichment of biofilm and exotoxin genes and a reduction in immune modulation, all exacerbating barrier dysfunction. Subsequent integrated correlation analysis linked the specifically enriched bacteria taxa, including Caldilinea sp. CFX5 and Ilumatobacter sp., to the upregulation of metabolic and virulence pathways, while also revealing significant microbiota–gene interactions that modulate gill immune and metabolic functions. Although previously reported pathogens like Flavobacterium and Aeromonas showed increased abundance in OWS-affected fish, their overall abundance remained low. Based on these findings, we propose a "Dysbiosis–Ferroptosis–Collapse" axis, in which microbiota-driven barrier disruption promotes iron overload and the suppression of GPX4, triggering non-resolving inflammation and ion dyshomeostasis. Targeting this cascade provides a novel theoretical framework for intervening in and developing new treatments for OWS.
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高影响因子
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