JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Wang Weilin,Hu Qiaoying,Wu Chunyan,Ding Jiayue,Zhu Chuanxiu,Wen Jiayao,Li Yingchao,Yang Menghan,Wang Yujie,Sun Deqing,Zhai Guangxi,Zhang Yanan
Ferroptosis and sonodynamic therapy (SDT) have both been recognized as powerful weapons in cancer treatment, especially in non-small-cell lung carcinoma (NSCLC) recently. However, the lack of effective sono-sensitizer and ferroptosis regulator limited their usage. In order to overcome the limitation, a novel nanoplatform of DTX-CS/ART/PFCA@RGD (cRCAPD) was fabricated based on SDT and ferroptosis. Nanoparticles, under the action of c(RGDfk) cyclic peptides and their skeleton chondroitin sulfate (CS), could specifically target αvβ3 and CD44 receptors, respectively, thereby targeting tumor sites. Meanwhile, the peroxy-bridge structure of ART disrupted the intracellular iron homeostasis while generating highly toxic reactive oxygen species (ROS) under the SDT. Docetaxel (DTX) in nanoparticles led to the excellent apoptosis of A549 cells. Oxygen carried by PFCA alleviated the tumor hypoxic microenvironment, downregulated HIF-1α, and provided substrates for SDT. Further, the nanoparticles showed a strong immunogenic cell death (ICD) effect, modulating the number of T cells and dendritic cells in tumor-bearing mice. In summary, the proposed therapeutic strategy based on SDT and ferroptosis holds promising potential for synergistic treatment of lung cancer in future clinical applications. Graphical The alternative text for this image may have been generated using AI.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Lin Lingting,Chen Binyu,Yang Yourui,Deng Ruocheng,Niu Wenfei,Liu Jian,Xu Wei,Li Hua
Background Proteolysis-targeting chimeras (PROTACs) have emerged as a promising cancer therapeutic approach by targeting protein degradation to address undruggable targets and drug resistance associated with conventional therapies, yet their clinical translation is hindered by poor solubility and non-specific toxicity. Additionally, tumor heterogeneity and biological complexity frequently limit the efficacy of monotherapies, necessitating the development of multifunctional delivery systems. Results We engineered a dual microenvironment-responsive albumin to integrate conditional PROTAC activation with metabolic starvation and ferroptosis for synergistic antitumor efficacy within a unified therapeutic cascade. Ferrocene (Fc)-modified human serum albumin (HSA) via coupling chemistry was electrostatically complexed with glucose oxidase (GOD) and co-assembled with an azobenzene (AZO)-caged ARV-771 prodrug to yield HSA-Fc-GOD@ARV-771(AZO) nanoparticles that exhibited pH-triggered disassembly in acidic tumor environments. the released GOD consumes glucose and oxygen to generate hydrogen peroxide while inducing metabolic starvation and exacerbating hypoxia. The intensified hypoxia triggers nitroreductase to cleave the prodrug linker and release the active ARV-771, which subsequently degrades bromodomain containing protein 4. This degradation directly suppresses tumor cell proliferation and downregulates glutathione peroxidase 4 expression to sensitize cancer cells to oxidative damage. Concurrently, the ferrocene component converts the generated hydrogen peroxide into hydroxyl radicals via the Fenton reaction to amplify lipid peroxidation and ferroptotic cell death. The nanoplatform suppressed lung cancer cell viability to 10.8% in vitro and achieved 94.3% tumor growth inhibition in xenograft models without observable systemic toxicity. Conclusions This study demonstrates a precision therapeutic paradigm. It exploits tumor microenvironment characteristics to couple conditional drug activation with starvation and ferroptosis. This strategy offers a translatable framework for next generation’s cancer treatment. Graphical
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JOURNAL OF CONTROLLED RELEASE
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2026
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IF 12.4
Weiqi Zhang,Linjia Chen,Yahui Dong,Yinghua Zeng,Yongyu Chen,Yue Liu,Jingru Wang,Fujun Shi
Triple-negative breast cancer (TNBC) remains a formidable clinical challenge due to the lack of druggable targets and intrinsic resistance to conventional therapies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, represents a promising therapeutic vulnerability in TNBC. Here, we identify solute carrier family 7 member 5 (SLC7A5) as a ferroptosis-suppressing prognostic target, and develop a tumor microenvironment (TME)-responsive camptothecin (CPT)-peptide conjugates (CPCs) nanoassembly for in situ delivery of the SLC7A5 inhibitor JPH203 to TNBC. The CPCs integrate an active tumor targeting motif, a CPT-based hydrophobic core that drives self-assembly, and a gelatinase-cleavable linker for enzyme-responsive disassembly. Upon TME-triggered release, JPH203 effectively blocks leucine uptake, suppresses mTORC1 signaling, disrupts iron and redox homeostasis, and synergizes with mitochondrial reactive oxygen species to induce potent ferroptosis, achieving an 81.2% tumor growth suppression rate in orthotopic 4 T1 models with favorable biosafety. Importantly, CPCs-JPH promotes dendritic cell maturation, activates CD8 + T-cell responses, and significantly improves survival outcomes in orthotopic 4 T1 tumor-bearing mice. This work establishes a multifunctional and enzyme-responsive nanoplatform that harnesses ferroptosis to overcome therapeutic resistance while concurrently engaging innate and adaptive immunity in TNBC.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Xiao Liang,Qi Huang,Yang Wu,Deyu Zhu,Zhuangzhuang Wei,Qing Feng,Zhilong Chen,Yibing Chen,Ping Ma,Xu Yang,Cuiyu Bao,Xinyu Bao
Background Polystyrene microplastics (PS-MPs) represent a major environmental contaminant, capable of building up in various organisms, including animals and plants. They can increase through the food chain, ultimately threatening human health. Recent research has indicated a possible association between exposure to PS-MPs in the environment and heart damage; nevertheless, the specific mechanisms behind this connection are not yet fully understood. Objectives This study aimed to investigate the toxic effects of PS-MPs exposure on cardiac health. We specifically elucidated the underlying mechanisms through which PS-MPs exacerbate doxorubicin hydrochloride (DOX)-induced cardiac injury, emphasizing oxidative stress, ferroptosis, and dysregulation of mitochondrial dynamics. Furthermore, we examined the protective effects of two antagonists: Ferrostatin-1 (Fer-1) and luteolin (Lut), against PS-MPs-induced cardiac injury. Methods C57BL/6 mice were categorized into eight distinct groups: the blank control group (saline), the PS-MPs exposure group (PS-MPs), the DOX modeling group (DOX), the combined exposure group of PS-MPs and DOX (PS-MPs+DOX), and the treatment groups with Fer-1 and Lut (PS-MPs+Fer-1, PS-MPs+Lut, PS-MPs+DOX+Fer-1, PS-MPs+DOX+Lut). The entire experimental duration spanned five weeks. We evaluated the effects of PS-MPs and DOX on cardiac function using electrocardiography and assessed their impact on cardiac injury through histopathological analysis of the heart. Concurrently, we examined the effects of PS-MPs and DOX on mitochondrial structure via mitochondrial electron microscopy. Furthermore, we analyzed the heart organ coefficient, myocardial injury markers (CK-MB, CTnT), oxidative stress biomarkers (ROS, MDA, GSH, 4-HNE, Nrf2), ferroptosis-related markers (Fe 2 + , GPX4, SLC7A11), mitochondrial damage markers (ATP, Complex III, Complex V), mitochondrial dynamics-related markers (OPA1, MNF2, DRP1), as well as serum metabolomics. Results Our findings reveal that exposure to PS-MPs exhibits significant cardiotoxic effects, influencing heart rate changes in mice and leading to abnormal in oxidative stress levels and ferroptosis-related proteins within myocardial tissue. Concurrently, exposure to PS-MPs leads to changes in mitochondrial structure and dynamics, further exacerbating oxidative stress and ferroptosis. Ultimately, PS-MPs aggravate DOX-induced cardiac injury. However, Fer-1 and Lut have a good improvement effect on the above situation. Furthermore, metabolomic analyses suggest that pathways and metabolites involved in cAMP signaling, the TCA cycle, tryptophan metabolism, and the metabolism of xenobiotics by cytochrome P450 may also play significant roles. Conclusion PS-MPs exposure can further exacerbate DOX-induced cardiac injury in mice, a process characterized by oxidative damage, activation of the ferroptosis pathway, and alterations in mitochondrial dynamics. Furthermore, luteolin, a naturally occurring active compound, plays a significant role in ameliorating this process.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Zhengwang Guo,Huifeng Hao,Xinxin Deng,Yanna Jiao,Bin Dong,Dong Xue,Shu-Yan Han
Ethnopharmacological relevance Triple-negative breast cancer (TNBC) has a poor clinical prognosis and shows resistance to traditional treatments. Ferroptosis is a potential therapeutic strategy for TNBC. Although dandelion extract has demonstrated anti-tumor effects against TNBC, its role in regulating ferroptosis has not been elucidated. Aim of the study This study aimed to investigate the role and mechanisms of dandelion extract in inhibiting TNBC via the induction of ferroptosis. Materials and methods Cell viability and cell death were detected by CCK-8 assay and PI/Hoechst 33342 dual staining, respectively. Proteomic profiling was used to identify the mechanisms of dandelion extract-induced cell death. Ferroptosis was assessed by measuring key hallmarks, including Fe 2+ accumulation, lipid peroxidation, mitochondrial dysfunction, and ultrastructural changes. Mechanistic validation was achieved through target-specific interference and subsequent biomolecular analysis. Results Dandelion extract selectively induced cell death in TNBC cells without affecting normal MCF-10A cells. Proteomic and experimental evidence indicates that dandelion extract induces ferroptosis in TNBC cells, characterized by elevated Fe 2+ , ROS, lipid peroxidation, MDA levels, and mitochondrial dysfunction. Crucially, ferroptosis inhibitors attenuated the inhibitory effect of dandelion extract on TNBC cell viability, confirming ferroptosis as the primary cell death mechanism. Mechanistic studies have demonstrated that dandelion extract promoted ferroptosis in TNBC cells both in vitro and in vivo through NCOA4-mediated ferritinophagy. Conclusions This study demonstrates that dandelion extract induces ferroptosis in TNBC cells both in vitro and i n vivo by regulating ferritinophagy mediated by the NCOA4-FTH1 axis, thus suggesting novel therapeutic strategies for TNBC treatment.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2023
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IF 9.9
Hui Cheng,Ye He,Junya Lu,Ziwei Yan,Luming Song,Yuling Mao,Donghua Di,Yikun Gao,Qinfu Zhao,Siling Wang
Glutathione (GSH) is a crucial factor in limiting the effects of chemodynamic therapy (CDT) and ferroptosis, an iron-based cell death pathway. Based on this, we constructed iron-rich mesoporous dopamine ( [email protected] ) nanovehicles with a dual-GSH depletion function by combining MPDA and Fe. Poly (ethylene glycol) (PEG) was further modified to provide desirable stability ( [email protected] ) and glucose oxidase (GOx) was grafted onto [email protected] ( [email protected] ) to address the limitation of hydrogen peroxide (H 2 O 2 ). After the nanoparticles reached the tumor site, the weakly acidic microenvironment promoted the release of Fe. Then Fe II reacted with H 2 O 2 to generate hydroxyl radical ( OH) and Fe III . The generated Fe III was reduced to Fe II by GSH, which circularly participated in the Fenton reaction and continuously produced tumor inhibitory free radicals . Meanwhile, GOx consumed glucose to provide H 2 O 2 for the reaction. MPDA had also been reported to deplete GSH. Therefore, dual consumption of GSH led to the destruction of intracellular redox balance and inhibition of glutathione-dependent peroxidase 4 (GPX4) expression, resulting in an increase in lipid peroxides (LPO) and further induction of ferroptosis. Additionally, MPDA-mediated photothermal therapy (PTT) raised the temperature of tumor area and produced photothermal-enhanced cascade effects. Hence, the synergistic strategy that combined dual-GSH depletion-induced ferroptosis, enhanced CDT and photothermal cascade enhancement based on [email protected] could provide more directions for designing nanomedicines for cancer treatment.
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CELL BIOLOGY INTERNATIONAL
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2022
·Vol. 47
·期 3
·598-611
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IF 4.473
Yangyang Wu,Shuo Zhou,An Zhao,Yuling Mi,Caiqiao Zhang
Oxidative stress is a major cause of ovarian aging and follicular atresia. There is growing evidence that showed potential roles of rutin in antidiabetic, anti-inflammatory, antitumor, antibacterial and antioxidant, although it is yet unclear what the underlying mechanism is. Here, we looked into the potential effects of rutin on oxidative stress in the prehierarchical small white follicles (SWFs) from 580-day-old (D580) laying chickens. According to the findings, aging D580 layer ferroptosis was much higher than it was for laying hens during the peak period (280-day-old, D280). In both naturally aged and d -gal-induced chicken SWFs, rutin treatment concurrently boosted cell proliferation and prevented apoptosis. In addition, rutin inhibited the increased ferroptosis in aging hens. Meanwhile, rutin markedly suppressed the elevated ferroptosis and descending antioxidant capacity of D280-culture-SWFs from chicken elicited by d -gal. Rutin's activation of the Nrf2/HO-1 pathway hastened the SWFs' verbal battle with oxidative damage and reduced ferroptosis. Furthermore, activation of the ferroptosis signal increased the oxidative damage in SWFs. In conclusion, rutin alleviated oxidative stress that was induced by ferroptosis in aging chicken SWFs through Nrf2/HO-1 pathway. These findings point to a novel mechanism by which rutin protects SWFs from oxidative stress by suppressing ferroptosis, which is presumably a fresh approach to slowing ovarian aging in laying hens.
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Acta Pharmaceutica Sinica B
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2022
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IF 14.903
Lujing Geng,Tong Lu,Huaqing Jing,Yue Zhou,Xiaoyang Liang,Jiao Li,Nan Li
Ferroptosis (FPT), a novel form of programmed cell death, is characterized by overwhelming iron/reactive oxygen species (ROS)-dependent accumulation of lipid peroxidation (LPO). However, the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent. To overcome this obstacle, the bromodomain-containing protein 4 (BRD 4 )-inhibitor (+)-JQ1 (JQ1) and iron-supplement ferric ammonium citrate (FAC)-loaded gold nanorods (GNRs) are encapsulated into the zeolitic imidazolate framework-8 (ZIF-8) to form matchbox-like [email protected] /ZIF-8 for the amplified FPT therapy. The existence of matchbox (ZIF-8) is stable in physiologically neutral conditions but degradable in acidic environment, which could prevent the loaded agents from prematurely reacting. Moreover, GNRs as the drug-carriers induce the photothermal therapy (PTT) effect under the irradiation of near-infrared II (NIR-II) light owing to the absorption by localized surface plasmon resonance (LSPR), while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment (TME). On one hand, the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron (Fe 3+ /Fe 2+ ) and ROS to initiate the FPT treatment by LPO elevation. On the other hand, JQ1 as a small molecule inhibitor of BRD 4 protein can amplify FPT through downregulating the expression of glutathione peroxidase 4 (GPX4), thus inhibiting the ROS elimination and leading to the LPO accumulation. Both in vitro and in vivo studies reveal that this pH-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility. As a result, our study points out a PTT combined iron-based/BRD 4 -downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.
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Cell Death & Disease
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2020
·Vol. 11
·期 3
·1-15
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IF 6.304
Zhang Changping,Liu Zixuan,Zhang Yuhao,Ma Liang,Song Erqun,Song Yang
Exposure to nanomaterials (NMs) is an emerging threat to human health, and the understanding of their intracellular behavior and related toxic effects is urgently needed. Ferroptosis is a newly discovered, iron-mediated cell death that is distinctive from apoptosis or other cell-death pathways. No evidence currently exists for the effect of “iron free” engineered NMs on ferroptosis. We showed by several approaches that (1) zinc oxide nanoparticles (ZnO NPs)-induced cell death involves ferroptosis; (2) ZnO NPs-triggered ferroptosis is associated with elevation of reactive oxygen species (ROS) and lipid peroxidation, along with depletion of glutathione (GSH) and downregulation of glutathione peroxidase 4 (GPx4); (3) ZnO NPs disrupt intracellular iron homeostasis by orchestrating iron uptake, storage and export; (4) p53 largely participates in ZnO NPs-induced ferroptosis; and (5) ZnO particle remnants and dissolved zinc ion both contribute to ferroptosis. In conclusion, our data provide a new mechanistic rationale for ferroptosis as a novel cell-death phenotype induced by engineered NMs.
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Frontiers in Cell and Developmental Biology
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2022
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IF 6.081
Fan Zhang,Hualong Zhen,Hengshun Cheng,Fengying Hu,Yunfei Jia,Binbin Huang,Minmin Jiang
As one kind of endocrine disrupting chemical, di-(2-ethylhexyl) phthalate (DEHP) has been reported to cause liver dysfunction in epidemiological and experimental studies. Abnormal liver function in pregnancy is associated with adverse maternal and perinatal outcomes. Few studies have investigated the potential effect of gestational DEHP exposure on the liver in pregnant mice, and the underlying mechanisms remain unclear. In the present study, pregnant ICR mice were exposed to doses (0, 500, 1,000 mg/kg/day) of DEHP in the presence or absence of 5 mg/kg/day ferrostatin-1 (Fer-1, ferroptosis inhibitor) by oral gavage from gestation day 4 to day 18. HepG2 cells were exposed to different doses of monoethylhexyl phthalate (MEHP, a major metabolite of DEHP) in vitro . Hepatic function and pathologic changes were observed. Oxidative stress, iron metabolism, and ferroptosis-related indicators and genes were evaluated both in vivo and in vitro . The results showed that gestational DEHP exposure induced disordered liver function and hepatocyte morphology changes in pregnant mice, along with increased malondialdehyde (MDA) and Fe 2+ content and decreased glutathione (GSH) levels. The expression levels of the selected ferroptosis-related genes Slc7a11 , Gpx4 , and Nfr2 were significantly decreased, and Ptgs2 and Lpcat3 were significantly increased. Notably, Fer-1 attenuated DEHP-induced liver injury and ferroptosis. Furthermore, MEHP exhibited a synergistic effect with RSL3 (a GPX4 inhibitor) in promoting ferroptosis in vitro . Taken together, the results demonstrated that DEHP induced liver injury and ferroptosis in pregnant mice, probably by inhibiting the GPX4 pathway through lipid peroxidation and iron accumulation.
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Nutrients
·
2022
·Vol. 14
·期 21
·4549
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IF 6.706
Tongtong Ba,Dai Zhao,Yiqin Chen,Cuiping Zeng,Cheng Zhang,Sai Niu,Hanchuan Dai
L-citrulline (L-cit) is a key intermediate in the urea cycle and is known to possess antioxidant and anti-inflammation characteristics. However, the role of L-cit in ameliorating oxidative damage and immune dysfunction against iron overload in the thymus remains unclear. This study explored the underlying mechanism of the antioxidant and anti-inflammation qualities of L-cit on iron overload induced in the thymus. We reported that L-cit administration could robustly alleviate thymus histological damage and reduce iron deposition, as evidenced by the elevation of the CD8+T lymphocyte number and antioxidative capacity. Moreover, the NF-κB pathway, NCOA4-mediated ferritinophagy, and ferroptosis were attenuated. We further demonstrated that L-cit supplementation significantly elevated the mTEC1 cells’ viability and reversed LDH activity, iron levels, and lipid peroxidation caused by FAC. Importantly, NCOA4 knockdown could reduce the intracellular cytoplasmic ROS, which probably relied on the Nfr2 activation. The results subsequently indicated that NCOA4-mediated ferritinophagy was required for ferroptosis by showing that NCOA4 knockdown reduced ferroptosis and lipid ROS, accompanied with mitochondrial membrane potential elevation. Intriguingly, L-cit treatment significantly inhibited the NF-κB pathway, which might depend on restraining ferritinophagy-mediated ferroptosis. Overall, this study indicated that L-cit might target ferritinophagy-mediated ferroptosis to exert antioxidant and anti-inflammation capacities, which could be a therapeutic strategy against iron overload-induced thymus oxidative damage and immune dysfunction.Keywords:L-citrulline;thymus;iron overload;ferritinophagy;ferroptosis
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Xuan Ma,Hui Chen,Lixing Cao,Shuang Zhao,Chong Zhao,Shutao Yin,Lihong Fan,Hongbo Hu
Ferroptosis is a new form of iron-dependent cell death . A growing body of evidence suggests that abnormal ferroptosis is involved in developing neurodegenerative diseases. 18β-glycyrrhetinic acid (GA) is a major bioactive component of licorice with multiple biological activities including neuroprotection. Give the role of ferroptosis in the neurodegenerative diseases, we hypothesized that the neuroprotective effect of GA might be associated with its ability to protect neuro-cells from ferroptosis. Results demonstrated that GA was able to prevent a well-known ferroptosis inducer ferroptosis inducer 56 (FIN56)-triggered ferroptosis in HT22 mouse neuronal cell. Further mechanistic investigation revealed that the protection of GA on ferroptosis is attributed its inhibiting effect on cellular labile iron accumulation and up-regulating coenzyme Q10 (CoQ10) levels. The findings of the present study uncovered a novel mechanism involved in the neuroprotective effect of GA, and imply that GA could be developed as a novel agent to manage ferroptosis-related diseases.
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