ACS Applied Materials & Interfaces
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2024
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IF 8.3
Wenyan Hao,Nan Sun,Yueyue Fan,Mengyu Chen,Qianqian Liu,Meiyan Yang,Yang Yang,Chunsheng Gao
Ferroptosis therapy and immunotherapy have been widely used in cancer treatment. However, nonselective induction of ferroptosis in tumors is prone to immunosuppression, limiting the therapeutic effect of ferroptosis cancer treatment. To address this issue, this study reports a customized hybrid nanovesicle composed of NK cell-derived extracellular versicles and RSL3-loaded liposomes (hNRVs), aiming to establish a positive cycle between ferroptosis therapy and immunotherapy. Thanks to the enhanced permeability and retention effect and the tumor homing characteristics of NK exosomes, our data indicate that hNRVs can actively accumulate in tumors and enhance cellular uptake. FASL, IFN-γ, and RSL3 are released into the tumor microenvironment, where FASL derived from NK cells effectively lyses tumor cells. RSL3 downregulates the expression of GPX4 in the tumor, leading to the accumulation of LPO and ROS, and promotes ferroptosis in tumor cells. The accumulation of IFN-γ and TNF-α stimulates the maturation of dendritic cells and effectively induces the inactivation of GPX4, promoting lipid peroxidation, making them sensitive to ferroptosis and indirectly promoting the occurrence of ferroptosis. This study highlights the role of the customized hNRV platform in enhancing the effectiveness of synergistic treatment with selective delivery of ferroptosis inducers and immune activation against glioma without causing additional side effects on healthy organs.
研究领域:
肿瘤学
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药理学
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纳米医学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Tongwang Luo,Shengzhe Song,Shujie Wang,Sheng Jiang,Bin Zhou,Quanjiang Song,Lingjun Shen,Xiaodu Wang,Houhui Song,Chunyan Shao
Cadmium (Cd), a pervasive environmental toxicant, poses significant threats to human and animal health through multi-organ toxicity. While ferroptosis has been implicated in Cd-induced pathologies, the molecular mechanisms underlying Cd-mediated nephrotoxicity remain poorly understood. This study elucidates the ferroptosis pathway in CdCl 2 -exposed PK-15 cells and murine kidney, characterized by iron overload, lipid peroxidation, and mitochondrial dysfunction, which were ameliorated by ferroptosis inhibitor ferrostatin-1. Transcriptomic analysis revealed substantial upregulation of heme oxygenase-1 (HO-1) following CdCl 2 exposure. Mechanistically, CdCl 2 triggered nuclear translocation of nuclear factor erythroid 2-related factor-2 (NRF2), subsequently activating HO-1 transcription. Over-activated HO-1 catalyzes the decomposition of heme and releases free iron, accompanied with the degradation of ferritin heavy chain 1 (FTH1) induced by CdCl 2 exposure, which leads to intracellular iron overload and excessive lipid peroxides production through Fenton reaction, resulting in ferroptosis ultimately. In vivo validation confirmed NRF2/HO-1-mediated ferroptosis in CdCl 2 -induced murine nephrotoxicity. Both pre-treatment with HO-1 competitive inhibitor Zinc protoporphyrin IX (ZnPP) and knockout of HO-1 gene remarkably alleviated PK-15 cells against ferroptosis induced by CdCl 2 treatment. Our findings demonstrate that Cd exposure initiates NRF2-mediated HO-1 overexpression, driving iron-dependent lipid peroxidation and subsequent ferroptosis. This mechanistic insight provides potential therapeutic targets for mitigating Cd-induced renal damage, advancing our understanding of heavy metal toxicity and its cellular consequences.
研究领域:
毒理学
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细胞生物学
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环境健康科学
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PubMed
高影响因子
Advanced Science
·
2023
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IF 15.1
Wei Chen,Wenyu Xie,Zhimin Gao,Chen Lin,Meiling Tan,Yaru Zhang,Zhiyao Hou
A core-shell-structured Cu 2 O@Mn 3 Cu 3 O 8 (CMCO) nanozyme is constructed to serve as a tumor microenvironment (TME)-activated copper ionophore to achieve safe and efficient cuproptosis. The Mn 3 Cu 3 O 8 shell not only prevents exposure of normal tissues to the Cu 2 O core to reduce systemic toxicity but also exhibits enhanced enzyme-mimicking activity owing to the better band continuity near the Fermi surface. The glutathione oxidase (GSHOx)-like activity of CMCO depletes glutathione (GSH), which diminishes the ability to chelate Cu ions, thereby exerting Cu toxicity and inducing cuproptosis in cancer cells. The catalase (CAT)-like activity catalyzes the overexpressed H 2 O 2 in the TME, thereby generating O 2 in the tricarboxylic acid (TCA) cycle to enhance cuproptosis. More importantly, the Fenton-like reaction based on the release of Mn ions and the inactivation of glutathione peroxidase 4 induced by the elimination of GSH results in ferroptosis, accompanied by the accumulation of lipid peroxidation and reactive oxygen species that can cleave stress-induced heat shock proteins to compromise their protective capacity of cancer cells and further sensitize cuproptosis. CMCO nanozymes are partially sulfurized by hydrogen sulfide in the colorectal TME, exhibiting excellent photothermal properties and enzyme-mimicking activity. The mild photothermal effect enhances the enzyme-mimicking activity of the CMCO nanozymes, thus inducing high-efficiency ferroptosis-boosted-cuproptosis.
研究领域:
纳米技术
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癌症生物学
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治疗学
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酶模拟
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光化学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Panpan Xue,Huilan Zhuang,Sijie Shao,Hai Cai,Shumin Tang,Ying Sun,Xuemei Zeng,Shuangqian Yan
Abnormal copper and iron ion metabolism promotes tumor proliferation but also presents a potential target for cancer therapy. However, simultaneously modulating these two ions is challenging, and the downstream therapeutic mechanisms remain unexplored. Here, we introduce Fe ss TMiR, a biodegradable ionic nanoregulator designed to modulate copper and iron ion homeostasis for tumor treatment. Fe ss TMiR comprises ferrous ions and disulfanediyldiacetic acid-assembled nanovectors (Fe ss NV) combined with tetrathiomolybdate (TM), an anti-copper agent. Under the acidic and high-glutathione conditions of the tumor microenvironment, Fe ss TMiR decomposes into ferrous ions and TM, leading to elevated iron and reduced copper levels. Transcriptome analysis reveals that this dual ion modulation induces cancer cell death via ferroptosis, apoptosis, and autophagy by affecting multiple pathways, including metal ion metabolism, glutathione metabolism, and oxidative stress. Additionally, Fe ss TMiR inhibits angiogenesis and reduces the expression of programmed cell death ligand 1 (PD-L1). Notably, Fe ss TMiR elicits robust antitumor immune responses in breast tumor mouse models, including dendritic cell maturation, Treg cell reduction, and enhanced T cell tumor infiltration. This study underscores the potential of modulating iron and copper homeostasis in tumor therapy, enhancement of antitumor immune responses, and activation of ferroptosis.
研究领域:
肿瘤学
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生物化学
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免疫学
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DOI
高影响因子
Journal of Environmental Sciences
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2025
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IF 6.3
Hongfei Hu,Guangji Wei,Hai Lan,Yang Feng,Shihua Luo,Yaqin Pang,Yanxin Huang,Huixiong Yuan,Huixin Peng,Wencheng Chen
The liver, a critical metabolic organ, is particularly vulnerable to damage upon aluminum exposure. However, the precise molecular mechanisms through which aluminum induces hepatotoxicity remain to be fully elucidated. This study aimed to investigate the adverse effects of aluminum exposure on mouse liver tissue. The results indicated that AlCl 3 exposure induced significant liver dysfunction, characterized by reduced adenosine triphosphate levels, elevated plasma alanine aminotransferase and aspartate aminotransferase. Histopathological analysis of liver tissue revealed marked histological damage, accompanied by substantial iron deposition. Further examinations demonstrated elevated hepatic levels of malondialdehyde, 4-hydroxynonenal, and reactive oxygen species, decreased levels of glutathione (GSH) and superoxide dismutase, increased levels of Oxidized glutathione (GSSG), and a reduced GSH/GSSG ratio. The mRNA and protein expression of ferroptosis-related molecules, including downregulated glutathione peroxidase 4 and solute carrier family 7 member 11, were significantly downregulated, while acyl-CoA synthetase long-chain family member 4, ferritin heavy chain 1, and iron regulatory protein 1 levels were significantly upregulated. Treatment with Ferrostatin-1 markedly ameliorated liver dysfunction and histopathological damage, attenuating signs of ferroptosis. These findings highlight the potential of ferroptosis-targeted therapies as a viable treatment strategy for aluminum exposure-induced hepatocyte injury.
研究领域:
毒理学
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肝脏病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-18
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IF 9.429
Luo Tao,Wang Yile,Wang Jinke
In 2020, nearly 20 million peoples got cancer and nearly 10 million peoples died of cancer, indicating the cancer remains a great threat to human health and life. New therapies are still in urgent demand. We here develop a novel cancer therapy named Ferroptosis ASsassinates Tumor (FAST) by combining iron oxide nanoparticles with cancer-selective knockdown of seven key ferroptosis-resistant genes (FPN, LCN2, FTH1, FSP1, GPX4, SLC7A11, NRF2). We found that FAST had notable anti-tumor activity in a variety of cancer cells but little effect on normal cells. Especially, FAST eradicated three different types of tumors (leukemia, colon cancer, and lung metastatic melanoma) from over 50% of cancer mice, making the mice survive up to 250 days without tumor relapse. FAST also significantly inhibited and prevented the growth of spontaneous breast cancer and improved survival in mice. FAST showed high pan anti-tumor efficacy, high cancer specificity, and in vivo safety. FAST defines a new form of advanced nanomaterials, advanced combinatorial nanomaterials, by combining two kinds of nanomaterials, a chemical nanomaterial (iron oxide nanoparticles) and a biochemical nanomaterial (adeno-associated virus), which successfully turns a general iron nanomaterial into an unprecedented assassin to cancer.
研究领域:
肿瘤学
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纳米技术
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分子生物学
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癌症疗法
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生物医学工程
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
He Xiaojun,Long Qiang,Zhong Yiming,Zhang Yecen,Qian Bei,Huang Shixing,Chang Lan,Qi Zhaoxi,Li Lihui,Wang Xinming,Yang Xiaomei,Dong Gao Wei,Ye Xiaofeng,Zhao Qiang
Background: Ferroptosis has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury and can be inhibited or promoted by ATF3. Short-chain fatty acids (SCFAs) have shown benefits in various cardiovascular diseases with anti-inflammatory and antioxidant effects. However, the impact of SCFAs on ferroptosis in ischemic-stimulated cardiomyocytes remains unknown. This study aimed to investigate the effect of SCFAs on cardiomyocyte ferroptosis, the expression of ATF3, and its potential upstream regulators.Methods and results: The expression of ATF3, ferroptosis pathway geneset (FPG), and geneset of potential regulators for ATF3 (GPRA, predicted by the PROMO database) was explored in the public human myocardial infarction single-cell RNA-seq (sma) dataset. Cardiomyocyte data was extracted from the dataset and re-clustered to explore the FPG, ATF3, and GPRA expression patterns in cardiomyocyte subclusters. A dose-dependent toxic experiment was run to detect the suitable dose for SCFA treatment. The erastin-induced ferroptosis model and hypoxia-reoxygenation (H/R) model (10 h of hypoxia followed by 6 h of reoxygenation) were adopted to assess the effect of SCFAs via the CCK8 assay. Gene expression was examined via RT-PCR and western blot. Ferroptosis markers, including lipid peroxides and Fe2+, were detected using the liperfluo and ferroOrange probes, respectively. In the sma dataset, upregulated ferroptosis pathway genes were mainly found in the infarction-stimulated cardiac cells (border zone and fibrotic zone), particularly the cardiomyocytes and adipocytes. The ATF3 and some of its potential transcription factors (VDR, EGR3, PAX5, and SP1) can be regulated by SCFA. SCFA can attenuate erastin-induced lipid peroxidation in cardiomyocytes. SCFA treatment can also reverse erastin-induced Fe2+ increase but may strengthen the Fe2+ in the H/R model. We also precisely defined a ferroptosis subcluster of cardiomyocytes (CM09) that highly expressed FPG, ATF3, and GPRA.Conclusion: The ATF3 and the ferroptosis pathway are elevated in cardiomyocytes of injury-related cardiac regions (border zone, ischemic zone, and fibrotic zone). SCFA can attenuate cardiomyocyte ferroptosis and regulate the expression of ATF3. Our study offers novel insights into the potential targets of SCFAs in the cardiovascular system.
研究领域:
心脏病学
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分子生物学
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
Cell Discovery
·
2025
·Vol. 11
·期 1
·1-17
·
IF 12.5
Shan Guangyao,Bian Yunyi,Sui Qihai,Liang Jiaqi,Ren Shencheng,Pan Binyang,Shi Haochun,Zheng Zhaolin,Zeng Dejun,Zhu Junkan,Chen Zhencong,Bi Guoshu,Fan Hong,Zhan Cheng
Lactylation, a lactate-mediated post-translational modification, has garnered significant attention for its pivotal role in epigenetic modulation. However, the intricate interplay between lactylation and ferroptosis in lung adenocarcinoma (LUAD) remains to be fully elucidated. Utilizing metabolomic profiling and comprehensive metabolic library screening, our study uncovers that ferroptosis markedly enhances lactic acid accumulation and subsequent protein lactylation, which in turn confers resistance to ferroptosis in LUAD cells. Functional assays, comprising cell viability tests, lipid peroxidation detection, as well as malondialdehyde and glutathione measurements, collectively reveal that SUMO2-K11 lactylation (SUMO2-K11la), the most prominently elevated lactylation in response to ferroptosis induction, serves as a pivotal factor in determining ferroptosis resistance. Sumoylation proteomics and co-immunoprecipitation assays reveal that SUMO2-K11la impairs the interaction between SUMO2 and ACSL4. Consequently, this disruption facilitates the degradation of ACSL4, thereby disrupting lipid metabolism and effectively mitigating ferroptosis. Furthermore, AARS1 is identified as the lactyltransferase and HDAC1 as the delactylase for SUMO2-K11la. Based on these findings, we develop a cell-penetrating peptide that competitively and specifically inhibits SUMO2-K11la. This peptide significantly potentiates ferroptosis and sensitizes LUAD to cisplatin in xenograft models, while enhancing chemoimmunotherapy responses in spontaneous lung cancer models. Overall, our findings imply that SUMO2-K11la is a pivotal regulator of ferroptosis resistance in LUAD, and suggest a promising strategy to potentiate ferroptosis-based cancer therapies via targeting SUMO2-K11la by the cell-penetrating peptide.
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PubMed
高影响因子
Cell Death & Disease
·
2025
·
IF 9.6
Ren Yuanyuan,Cui Yue,Wang Zhen,Luo Yizhi,Jin Junchang,Yuan Yiyi,Li Xuan,Zhang Yaning,Cao Nan,Li Xiaofang,Yu Yi,Xiong Yuyan
Gastric cancer (GC) is a prevalent gastrointestinal malignancy in which ferroptosis, mitochondrial dysfunction, and macrophage reprogramming remarkably contribute to disease progression. However, the molecular interplay among these processes in contributing to GC remains poorly understood. In this study, we identified ferroptosis- and mitochondrial dysfunction-related genes (FMDRGs) implicated in GC through bioinformatics analyses. Among them, aldehyde dehydrogenase 3 family member A2 (ALDH3A2) was identified as a key FMDRG significantly downregulated in GC tissues and cell lines. Functional assays revealed that ALDH3A2 overexpression in GC cell lines suppressed proliferation, migration, and invasion while enhancing ferroptosis, effects that were reversed by GPX4 overexpression. ALDH3A2 also impaired the mitochondrial unfolded protein response (UPR mt ) and induced mitochondrial dysfunction. Restoration of UPR mt ameliorated ALDH3A2-induced mitochondrial dysfunction and ferroptosis. Mechanistically, ALDH3A2 impaired UPR mt by downregulating SLC47A1 through blockade of NRF2 nuclear translocation, leading to mitochondrial dysfunction, GPX4 downregulation, lipid peroxidation, and subsequent ferroptosis. Synergistically, ALDH3A2-induced ferroptosis promoted IL-6 release, which drove macrophage polarization toward the M1 phenotype with elevated IL-1β production. This macrophage reprogramming, in turn, inhibited GC cell progression by downregulating PD-L1 expression. Therapeutically, both genistein treatment and ALDH3A2 overexpression significantly attenuated GC progression in vitro and in vivo. These findings elucidate ALDH3A2 as a dual regulator of tumor-intrinsic ferroptosis and tumor-extrinsic immune remodeling in contributing to GC pathogenesis, highlighting its potential as a promising therapeutic target in GC.
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
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IF 12.5
Peng Ye,Tianyu Su,Kai Wang,Dehong Yu,Minghao Chao,Liying Fan,Guoquan Wu,Guanghui Wang,Fenglei Gao,Lei Hua
RNA interference (RNAi) technology, which silences disease-causing genes, offers a novel therapeutic approach for glioblastoma (GBM). However, the clinical translation of small interfering RNA (siRNA) faces challenges such as low delivery efficiency, rapid renal clearance, and endosomal/lysosomal entrapment. This study developed a dual-targeted nanoplatform FZMT, enable precise siRNA delivery while synergistically inducing ferroptosis and antitumor immunity. Under magnetic guidance, FZMT traverses the blood-brain barrier (BBB) and accumulates in tumors via TPP-mediated active targeting. Within the acidic tumor microenvironment, Fe 3 O 4 releases Fe ions that trigger Fenton reactions, depleting glutathione (GSH) and inducing lipid peroxidation (LPO). Concurrently, ZIF-8 degradation releases siMDM2 to silence MDM2, restoring p53 (TP53) function to suppress the SLC7A11-GPX4 axis and amplify ferroptosis. Furthermore, Zn 2+ and siMDM2 cooperatively activate the cGAS-STING pathway, promoting type I interferon secretion. The release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) reprograms the immunosuppressive microenvironment, enhancing dendritic cell (DC) maturation and adaptive immunity. Experimental results demonstrate that FZMT significantly suppresses GBM progression through a multi-cascade mechanism involving “magnetic targeting-molecular recognition-gene silencing-ferroptosis-immune activation”. This study presents an innovative strategy to overcome siRNA delivery barriers and achieve multimodal therapy for tumors, providing a promising paradigm for GBM treatment.
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2026
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IF 8.7
Runlin Gui,Yang Li,Liyao Zhang,Junchang Jin,Yuqi Shi,Junxuan Wang,Jingyu Guo,Lu Qian,Yuyan Xiong
Obesity is closely linked to the development of non-alcoholic fatty liver disease (NAFLD), yet its mechanisms are not fully understood. Ethanolamine phosphate phospholyase (ETNPPL), an enzyme highly expressed in the liver, catalyzes the conversion of phosphoethanolamine to ammonia, inorganic phosphate, and acetaldehyde. This study shows that ETNPPL plays a crucial role in obesity-associated NAFLD by regulating lipid accumulation, liver dysfunction, and lipid homeostasis. ETNPPL expression was increased in high-fat diet (HFD)-induced NAFLD mice, while its deficiency alleviated NAFLD. ETNPPL overexpression and free fatty acids (FFAs) exposure promoted ferroptosis in hepatocytes. The FFAs-ETNPPL signaling axis induces lipid accumulation and dysfunction through ferroptosis via the GPX4/mtROS pathway and the inhibition of ALDH2. Moreover, FFAs-induced hepatocyte ferroptosis reprogrammed macrophages, exacerbating liver dysfunction. In vivo, ETNPPL knockout reduced hepatic ferroptosis and macrophage reprogramming in mice. These findings highlight ETNPPL as a potential therapeutic target for obesity-related NAFLD.
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Xiangyu Jin,Didi Liu,Yitan Su,Ting Xue,Tengchuan Jin,Yi Huang
We identify oridonin induces ferroptosis through high throughput screening. • We found oridonin covalently binds to cysteine to block glutathione synthesis via its α, β-unsaturated carbonyl group. • We developed a tumor-targeting and hypoxia-responsive nanoparticle platform to deliver oridonin to achieve specific induction of tumor cells ferroptosis in vivo. • We found oridonin inhibits tumor growth and enhances antitumor immunity in various animal tumor models of colorectal cancer transplants and metastases. Ferroptosis, an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxidation and iron, has emerged as a compelling vulnerability for cancer therapy. However, the scarcity of potent ferroptosis inducers with favorable pharmacological properties and their limited ability to reshape the immunosuppressive tumor microenvironment (TME) remain significant challenges. Here, we identify Oridonin (Ori), the major active component of the traditional Chinese medicine Rabdosia rubescens , as a novel and potent ferroptosis inducer through high-throughput screening (HTS). Mechanistically, we reveal that Ori covalently binds to cysteine to impair glutathione (GSH) biosynthesis, thereby triggering lipid peroxidation and ferroptosis. Notably, the α, β-unsaturated carbonyl group within Ori is identified as the critical pharmacophore for the ferroptosis-inducing effect. Considering that the therapeutic efficacy of Ori in vivo is greatly limited by its poor water solubility and tumor targeting ability, we engineer a tumor-targeting and hypoxia-responsive nanoparticle platform to deliver Ori (Ori-NP) to enable precise intratumoral release. Our results demonstrate that Ori-NP effectively suppresses tumor progression by inducing tumor cells ferroptosis mediated by ACSL4. Beyond direct cytotoxicity, Ori-NP serves as a potent immunomodulator that remodels the immunosuppressive TME by promoting dendritic cell maturation and enhancing CD8 + T cell infiltration. Consequently, the combination of Ori-NP with anti-PD-1 antibodies yields a potent synergistic antitumor effect. Overall, our research provides a powerful therapeutic strategy to harness ferroptosis for synergistic cancer immunotherapy.
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高影响因子
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