JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Jingting Li,Sihan Wang,Fan Yang,Yang Guo,Xinyu Gao,Mingyu Nie,Zihan Zhou,Hao Xin,Fei Song,Changsong Dai,Zhaohui Wen
Background: Single-atom nanozymes (SAzymes) generally trigger catalytic reactions in situ within tumor cells, generating toxic reactive oxygen species (ROS) that induce cell death through oxidative stress, thereby achieving catalytic tumor therapy. However, therapeutic efficacy is often limited by insufficient ROS levels and intrinsic cellular antioxidant defenses. Results: This study developed a spherical mesoporous iron-based single-atom nanozyme (Fe-SAzyme) modified with polyethylene glycol (PEG) and (4-carboxybutyl)triphenylphosphonium bromide (TPP), achieving photothermal amplification of catalytic activities to deliver antitumor therapeutic effects. Fe-SAzyme exhibited triple enzyme-mimetic activities-peroxidase-like, glutathione peroxidase-like, and catalase-like activity. It simultaneously generated ROS and oxygen while oxidizing glutathione to oxidized glutathione. This elevation in ROS levels and weakening of antioxidant defenses disrupted intracellular redox homeostasis, ultimately triggering a process known as ferroptosis. Density functional theory (DFT) calculations revealed that Fe-SAzyme exhibited a low energy barrier for hydroxyl radical generation and possessed a viable cyclic catalytic pathway. Additionally, Fe-SAzyme-TPP exhibited exceptional photothermal conversion capabilities under second near-infrared (NIR-II) irradiation, enabling its use in photothermal therapy (PTT), while simultaneously enhancing catalytic activity and thereby significantly improving tumor treatment efficacy. In vitro and in vivo experiments demonstrated that PEG and TPP-modified Fe-SAzyme exhibited outstanding antitumor efficacy, along with enhanced biocompatibility and targeting capabilities. Under NIR-II irradiation, photothermal therapy synergized with catalytic activities, significantly amplifying tumor suppression effects. Conclusion: This study proposed a combined antitumor strategy based on iron-based SAzymes, utilizing photothermal amplification to enhance catalytic activities in conjunction with PTT, thereby achieving ferroptosis-based antitumor effects.
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BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Qiyu Zhu,Zhifa Wang,Lu Xia,Fengzhuo Zhou,Zhishuai Zhou,Junfang Sun,Yulu Li,Lunxu Wang,Yunhao Li,Liuyang Yan,Wei Mei,Qingling Yang,Mingliang Zhang,Wenrui Wang
Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options and poor prognosis, creating an urgent demand for novel strategies. Sonodynamic therapy (SDT) is a promising non-invasive approach, yet its clinical translation is restricted by low efficacy of traditional sonosensitizers and single-modal limitations. In this study, we constructed a zinc‑copper‑iron-based layered double hydroxide (ZnCuFe@LDHs) nanoplatform integrating SDT with synergistic ferroptosis and cuproptosis for targeted TNBC treatment. In vitro experiments with 4 T1 cells demonstrated efficient cellular internalization and lysosomal escape of ZnCuFe@LDHs. Under ultrasound stimulation, the nanoplatform generated abundant reactive oxygen species (ROS) and released Cu 2+ /Fe 3+ in response to the acidic tumor microenvironment (TME) and elevated intracellular glutathione (GSH). These events synergistically triggered ferroptosis by inactivating glutathione peroxidase 4 (GPX4) and accumulating lipid peroxide, while inducing cuproptosis through Cu 2+ overload, mitochondrial dysfunction, tricarboxylic acid cycle disruption and lipoylated dihydrolipoamide acetyltransferase (DLAT) oligomerization. Additionally, ZnCuFe@LDHs triggered immunogenic cell death (ICD) characterized by calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release, promoting dendritic cell maturation and antitumor immunity. In vivo studies using 4 T1 subcutaneous xenograft models confirmed significant tumor growth suppression by ZnCuFe@LDH and ultrasound, with no obvious systemic toxicity. Serum biochemical analysis and histological examination of major organs validated favorable biocompatibility. Collectively, ZnCuFe@LDHs achieves potent targeted antitumor efficacy via the integration of SDT, ferroptosis, cuproptosis, andimmunogenic cell death(ICD). This quadruple-modal synergistic strategy offers a safe and translational therapeutic option for TNBC.
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ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Zijia Jiang,Yifan Zhao,Zequn Li,Huimei Jiang,Bai Lv,Jie Cao
Photodynamic therapy (PDT) faces significant challenges in clinical applications, including tumor hypoxia, the poor water solubility of photosensitizers, and insufficient targeting specificity. To address these limitations, we developed a biomimetic nanoagonist, 4T1@MFCB, by coloading a near-infrared photosensitizer (CyI) and a GLUT1 inhibitor (BAY-876) into a manganese/iron bimetallic metal–organic framework (MOF), followed by coating with the homologous 4T1 cell membrane. The manganese component catalyzes the decomposition of endogenous H2O2 to generate oxygen, alleviating tumor hypoxia and enhancing PDT efficacy, while the iron component promotes ferroptosis via the Fenton reaction. Meanwhile, BAY-876 inhibits glucose uptake, disrupting NADPH production and the cystine-to-cysteine reduction process, which leads to cystine accumulation and glutathione (GSH) depletion. These effects collectively suppress the Solute Carrier Family 7 Member 11(SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) antioxidant axis, thereby triggering disulfidptosis. Under near-infrared irradiation, CyI mediates effective photodynamic and photothermal therapy (PTT). Both in vitro and in vivo studies demonstrate that 4T1@MFCB enables synergistic PDT/ferroptosis/disulfidptosis therapy, significantly inhibiting tumor growth without obvious systemic toxicity. This work highlights a multimodal treatment strategy that integrates metabolic intervention with nanocatalytic therapy, providing a promising approach for the precision treatment of hypoxic and therapy-resistant tumors.
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DRUG RESISTANCE UPDATES
·
2026
·
IF 21.7
Lianli Ni,Hailong Li,Peipei Chen,Yun Yu,Chenjun Xie,Wenfeng Hong,Gaowei Fang,Baohong Wan,Yiwei Shen,Peng Zou,Wangyu Zhu,Zhiguo Liu,Xiaokun Li,Ri Cui
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and the leading cause of cancer-related deaths globally. The RNA binding protein Quaking-5 (QKI-5) has been established as a tumor suppressor in NSCLC. Inducing ferroptosis is regarded as an effective therapeutic strategy for cancer treatment, and long non-coding RNA (lncRNA) plays a critical role in the regulation of ferroptosis. However, the relationship between QKI-5-regulated lncRNA and ferroptosis remains uncharacterized in NSCLC. In this study, we discovered that QKI-5 downregulates the oncogenic lncRNA linc01833, which inhibits ferroptosis and promotes NSCLC progression by activating SLC7A11/GPX4 signaling pathway. Mechanistically, QKI-5 negatively regulates the stability of linc01833, leading to increased linc01833 expression in NSCLC. Silencing linc01833 enhanced WW domain-containing E3 ubiquitin protein ligase 1 (WWP1)-mediated ubiquitination of SLC7A11, resulting in decreased SLC7A11 expression, while overexpression of linc01833 produced the opposite effect. Further analyses demonstrated that linc01833 diminished the anti-tumor effect of gemcitabine (GEM) in NSCLC both in vivo and in vitro . Additionally, knocking down linc01833 or SLC7A11 is able to inhibit GEM resistant NSCLC growth. Our findings suggest that targeting linc01833 to induce ferroptosis could enhance the cytotoxic effects of chemotherapeutic agents and may serve as an effective therapeutic strategy for some NSCLC patients.
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TISSUE & CELL
·
2023
·
IF 2.6
Lei Huang,Mengxuan Bian,Shunyi Lu,Jiayi Wang,Jieqin Yu,Libo Jiang,Jian Zhang
Ferroptosis is a novel form of cell death, which is a unique modality of cell death and closely associated with iron concentrations, generation of reactive oxygen species (ROS), and accumulation of the lipid reactive oxygen species. In the present study, the anti-ferroptosis effects of Engeletin was studied in erastin-induced bone marrow mesenchymal stem cells (BMSCs). After treatment with Engeletin, cell viability was determined by CCK-8 assay. The production of ROS, malonaldehyde (MDA), Superoxide dismutase (SOD) activities and glutathione peroxidase (GSH) were detected by using commercially-available kits. Ferroptosis-related proteins (GPX4, SLC7A11, TFR1, FPN1, Nrf2, Keap1) were evaluated by Western blotting. Osteogenic capacity was evaluated by ALP staining and ARS staining. The expression of osteogenic-related proteins (OPN, Runx2, OCN) were evaluated by Western blotting and changes in mRNA (ALP, BMP-2, COL-1, Osterix) were evaluated by RT-PCR. Consistent improvements in angiogenesis are observed with Engeletin in the presence of erastin. Engeletin significantly alleviated erastin-induced oxidative damage and protected against ferroptosis in BMSCs. Ferroptosis was inhibited by Engeletin, leading to decreasing reducing accumulation of ROS and lipid peroxidation products. Moreover, Engeletin promoted osteogenic differentiation in BMSCs and angiogenesis in human umbilical vein endothelial cells (HUVECs). Taken together, these findings indicate that Engeletin can protect BMSCs from erastin-induced ferroptosis through the Nrf2/Keap1 antioxidant pathway and identify Engeletin as a novel ferroptosis inhibitor, suggesting that Engeletin may promote resistance to ferroptosis and enable osteogenic function of BMSCs.
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Cell Death Discovery
·
2022
·Vol. 8
·期 1
·1-10
·
IF 7.109
Wang Jingyu,Wang Yaqing,Liu Yi,Cai Xintian,Huang Xin,Fu Wenjing,Wang Lei,Qiu Lihua,Li Junying,Sun Li
Ferroptosis is a non-traditional form of regulated cell death, characterized by iron overload and lipid peroxidation. Exploration of ferroptosis in chronic kidney disease (CKD) has been extremely limited to date. In this study, we established a rat model of CKD by 5/6 nephrectomy, treated CKD rats with the ferroptosis inducer, cisplatin (CDDP), and the ferroptosis inhibitor, deferoxamine mesylate (DFO), and observed the resulting pathologic changes (injury markers and fibrosis) and ferroptotic biochemical indices. Kidney iron deposition, lipid peroxidation, mitochondrial defects, ferroptosis marker induction, and TUNEL staining positivity were detected in CKD group rats. Further, treatment with CDDP or DFO influenced renal injury and fibrosis by affecting ferroptosis, rather than apoptosis, and ferroptosis occurs in the remnant kidney due to disordered iron metabolism. In conclusion, our study shows for the first time that 5/6 nephrectomy induces ferroptosis in the remnant kidney and clarifies the underlying pathogenesis. Moreover, we demonstrate that ferroptosis is involved in CKD progression and represents a therapeutic target in chronic kidney injury and renal fibrosis.
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DRUG DELIVERY
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2022
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IF 6.819
Zhian Chen,Zhenhao Li,Chuangji Li,Huilin Huang,Yingxin Ren,Zhenyuan Li,Yanfeng Hu,Weihong Guo
Gastric cancer (GC) is a serious disease with high morbidity and mortality rates worldwide. Chemotherapy plays a key role in GC treatment, while inevitable drug resistance and systematic side effects hinder its clinical application. Fenton chemistry-based chemodynamic therapy (CDT) has been used as a strategy for cancer ferroptosis, and the CDT efficiency could be enhanced by photothermal therapy (PTT). With the trend of treatment and diagnosis integration, the combination of magnetic resonance imaging (MRI) and CDT/PTT exhibits enormous progress. Herein, we constructed a platform based on PEGylated manganese-containing polydopamine (PDA) nanoparticles, named as PEG-PDA@Mn (PP@Mn) NPs. The PP@Mn NPs were stable and globular. Furthermore, they demonstrated near-infrared (NIR)-triggered PTT and Fenton-like reaction-based CDT effects and T1-weighted MRI capabilities. According to in vitro studies, the PP@Mn NPs trigger ferroptosis in cancer cells by producing abundant reactive oxygen species (ROS) via a Fenton-like reaction combined with PTT. Furthermore, in vivo studies showed that, under MRI guidance, the PP@Mn NPs combined with the PTT at the tumor region, have CDT anti-tumor effect. In conclusion, the PP@Mn NPs could provide an effective strategy for CDT/PTT synergistic ferroptosis therapy for GC.
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FEBS Open Bio
·
2021
·Vol. 11
·期 8
·2118-2126
·
IF 2.693
Na Wei,Tan Lu,Libin Yang,Yonghan Dong,Xiaotan Liu
Ferroptosis is an iron-dependent programmed cell death, which participates in the pathogenesis of spinal cord injury (SCI). Our previous study has revealed that Lipoxin A4 (LXA4) exerts a protective role in SCI. Here, we investigated whether LXA4 can protect SCI through inhibiting neuronal ferroptosis. We treated primary spinal cord neurons with Erastin (ferroptosis activator) to induce ferroptosis. Erastin treatment reduced cell viability and enhanced cell death of primary spinal cord neurons, which was rescued by ferrostatin-1 (ferroptosis inhibitor). Moreover, Erastin repressed glutathione peroxidase 4 (GPX4) expression and the levels of glutathione and cysteine in primary spinal cord neurons. Erastin also enhanced the expression of ferroptosis biomarkers (PTGS2 and ACSL4) and the levels of reactive oxygen species (ROS) in primary spinal cord neurons. The influence conferred by Erastin was effectively abolished by LXA4 treatment. Furthermore, LXA4 enhanced the protein expression of p-AKT, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and haem-oxygenase-1 (HO-1) in primary spinal cord neurons. LXA4-mediated inhibition of ferroptosis of primary spinal cord neurons was prohibited by LY294002 (AKT inhibitor), brusatol (Nrf2 inhibitor) or zinc protoporphyrin (HO-1 inhibitor). In conclusion, this work demonstrated that LXA4 exerted a neuroprotective effect in Erastin-induced ferroptosis of primary spinal cord neurons by activating the Akt / Nrf2 / HO-1 signaling pathway. Thus, this work provides novel insights into the mechanisms of action of LXA4 in ferroptosis of primary spinal cord neurons and indicates that LXA4 may be a potential therapeutic agent for SCI.
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ACS Applied Materials & Interfaces
·
2019
·
IF 8.456
Mangmang Sang,Renjie Luo,Yidan Bai,Jun Dou,Zhongtao Zhang,Fulei Liu,Feng Feng,Wenyuan Liu
Ferroptosis is an iron-dependent cell death caused by accumulation of lipid peroxidation (LPO), which is a new strategy for cancer treatment. Th current ferroptosis therapy nanodevices have low efficiency and side effects generally. Hence, we developed a Black Hole Quencher (BHQ)-based fluorescence “off–on” nanophotosensitizer complex assembly (CSO-BHQ-IR780-Hex/MIONPs/Sor). CSO-connected BHQ-IR780-Hex and -loaded magnetic iron oxide nanoparticles (MIONPs) and sorafenib (Sor) formed a very concise functionalized delivery system. CSO-BHQ-IR780-Hex disassembled by GSH attack and released IR780-Hex, MIONPs, and sorafenib. IR780-Hex anchored to the mitochondrial membrane, which would contribute to amplifying the efficiency of the photosensitizer. When NIR irradiation was given to CSO-BHQ-IR780-Hex/MIONPs/Sor-treated cells, iron supply increased, the xCT/GSH/GPX-4 system was triggered, and a lot of LPO burst. A malondialdehyde test showed that LPO in complex assembly-treated cells was explosive and increased about 18-fold compared to the control. The accumulation process of particles was monitored by an IR780-Hex photosensitizer, which showed an excellent tumor target ability by magnetic of nanodevice in vivo. Interestingly, the half-life of sorafenib in a nanodevice was increased about 26-fold compared to the control group. Importantly, the complex assembly effectively inhibits tumor growth in the breast tumor mouse model. This work would provide ideas in designing nanomedicines for the ferroptosis treatment of cancer.
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CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Zhijing He,He Zhou,Qixiang Feng,Yu Zhang,Shan Gao,Shangui Liu,Lei Ye,Jianbo Ji,Yanwei Xi,Xiaoye Yang,Guangxi Zhai
Restricted by the complex intracellular ferroptosis regulatory networks, single ferroptotic therapy against breast cancer (BC) yields limited therapeutic outcomes. Therefore, novel combination modes are being widely attempted; however, the interactions between different treatments are still less studied. Herein, we propose a combinational pattern by constructing a novel nanoplatform (T-FeCo/P) composed of Panobinostat (histone deacetylase inhibitor)-loaded iron (Fe)/cobalt (Co)-based metal–organic framework with surface modification of telmisartan for dual 4 T1 cell/cancer-associated fibroblast (CAF) targeting. T-FeCo/P exhibits good photothermal performance and forcefully triggers cellular ferroptosis, and the dopant of Fe realizes stronger ferroptosis activation than the corresponding single-metal system. Interestingly, for the first time, Panobinostat is elucidated to promote ferroptosis by inhibiting SLC7A11 transcription and regulating thioredoxin binding protein 2 (TBP2)/thioredoxin (Trx) axis. For tumor microenvironment (TME) remodeling, T-FeCo/P specifically kills CAFs, thus destroying extracellular matrix and retarding C-X-C motif chemokine ligand 12 (CXCL12) secretion, which are beneficial to intratumoral drug penetration and cytotoxic T lymphocyte infiltration. Also, this CAF elimination probably sensibilizes ferroptosis by regulating neurofibromatosis type 2 (NF2)-yes associated protein (YAP) pathway and reducing myeloid-derived suppressor cell infiltration. Our experimental data support T-FeCo/P’s tumoricidal activity thanks to the combined ferroptosis activation, epigenetic regulation, photothermal therapy and TME re-education, providing a mighty pattern for BC treatment and constituting a substantial addition to ferroptosis sensitization.
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CELLULAR ONCOLOGY
·
2023
·
IF 6.6
Wei Wanhui,Lu Yuanyuan,Hu Qian,Yin Jinwen,Wang Youwei,Zhang Heng,Zhao Qiu,Liu Lan
Purpose The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. Methods First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC–MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. Results Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. Conclusions In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.
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PHYTOTHERAPY RESEARCH
·
2023
·
IF 7.2
Man Hu,Wen Jiang,Chen Ye,Ting Hu,Qingqing Yu,Moran Meng,Lijuan Sun,Jichao Liang,Yong Chen
Schwann cells injury induced by high glucose (HG) contributes to the development of diabetic peripheral neuropathy (DPN). Honokiol has been reported to regulate glucose metabolism, however, its effect on DPN and the precise molecular mechanisms remain unclear. This study aimed to investigate the role of AMPK/SIRT1/PGC-1α axis in the protective effects of honokiol on DPN. The biochemical assay and JC-1 staining results demonstrated that honokiol reduced HG-induced oxidative stress and ferroptosis as well as mitochondrial dysfunction in Schwann cells. RT-qPCR and western blotting were utilized to investigate the mechanism of action of honokiol, and the results showed that HG-induced inhibition of AMPK/SIRT1/PGC-1α axis and changes of downstream gene expression profile were restored by honokiol. Moreover, silencing of Sirt1 by siRNA delivery markedly diminished the changes of gene expression profile induced by honokiol in HG-induced Schwann cells. More importantly, we found that administration of honokiol remarkably attenuated DPN via improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity in streptozotocin-induced diabetic rats. Collectively, these results demonstrate that honokiol can attenuate HG-induced Schwann cells injury and peripheral nerve dysfunction, suggesting a novel potential strategy for treatment of DPN.
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