ACS Nano
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2024
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IF 15.8
Shuheng Qin,Hui-yue Zhao,Xing-yu Luo,Fei Wang,Jun Liu,Yin Ding,Yong Hu
The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes’ activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal–organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H2O2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H2O2 is generated during this procedure, which can endogenously replenish the consumed H2O2. Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H2O2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.
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PubMed
高影响因子
Redox Biology
·
2025
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IF 11.9
Xue Shi,Yun Zhao,Hong-Yu Gao,Wei Yang,Jun Liao,Hui-Han Wang,Xiao-Tian Wang,Wei Yan
Diffuse large B cell lymphoma (DLBCL) is a common hematologic malignancy. NFS1 cysteine desulfurase, as a rate-limiting enzyme in the iron-sulfur cluster (ISC) biogenesis, has been reported to be associated with tumor progression. However, the role of NFS1 in DLBCL remains elusive. Here, we showed an upregulation of NFS1 in DLBCL tumor tissues. Knockdown of NFS1 decreased the cell viability and enhanced LDH levels in DLBCL cells. Animal experiments further indicated that downregulation of NFS1 suppresses tumor growth in vivo. NFS1 knockdown increased the lipid reactive oxygen species (ROS) level in cells, and this promotional effect was reversed by ferroptosis inhibitors, but not influenced by other types of cell death inhibitors. This result suggested that NFS1 depletion-impaired cell viability is associated with ferroptosis. Silenced NFS1 aggravated ferroptosis inducers caused cell viability inhibition, lactate dehydrogenase (LDH), and lipid ROS levels enhancement, while the addition of ferroptosis inhibitors abated these trends. Moreover, catalytic residue mutation of NFS1 did not affect its protein expression but decreased the cell viability, which was promoted by NFS1 upregulation, indicating that the protective effect of NFS1 in DLBCL cells was related to its catalytic activity. Further results showed that frataxin (FXN), the upstream activator of NFS1, reduced the cell viability in NFS1 upregulated cells. Consistent with NFS1, FXN silencing aggravated erastin-induced cell viability inhibition and LDH level enhancement. Silencing NFS1 or FXN inhibited the level of iron ions storage-related proteins but promoted the level of transport-related proteins. In addition, silenced NFS1 or FXN displayed an inhibition effect on protein expression of DNA polymerases, but a promotion trend in the phosphorylation of DNA damage markers. In conclusion, we demonstrated that ISC-related proteins NFS1 and FXN protect DLBCL cells from ferroptosis and DNA damage, thus exhibiting an essential role in DLBCL progression.
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高影响因子
ACS Applied Nano Materials
·
2025
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IF 5.5
Xiaoli Bao,Xiuqing Liao,Zhongqiang Zhu,Ling Jiang,Daoxin Wang
Acute lung injury (ALI) represents a life-threatening condition with limited therapeutic options. Emerging evidence suggests that ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, is a key pathological mechanism underlying ALI. Therefore, we systematically investigated the key role of ferroptosis in ALI pathogenesis using a lipopolysaccharide (LPS)-induced mouse model of sepsis-related ALI. Based on this finding, we engineered polyvinylpyrrolidone-assembled cobalt hexacyanoferrate nanocatalysts (CoHCF NCs) as a ferroptosis inhibitor. These nanocatalysts exhibited dual functions: efficient chelation of free iron ions and strong antioxidant activity. In vivo experiments showed the promising therapeutic efficacy of CoHCF NCs, while in vitro studies using erastin-induced ferroptosis in alveolar epithelial cells confirmed their strong ability to reverse ferroptotic processes. To explore the underlying mechanisms, we employed RNA sequencing, which revealed that CoHCF NCs exert their antiferroptotic effects through a transcriptional network involving antioxidant response enhancement, and iron ion homeostasis regulation. Due to their high ferroptosis-inhibitory capacity and biocompatibility, CoHCF NCs represent a promising therapeutic candidate for ALI.
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Bioactive Materials
·
2025
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IF 20.3
Yi Wang,Xuemei Liao,Qinglong Guo,Heng Zhang,Lei Ye,Liangchen Yu,Xiaoming Kong,Yicheng Jiang,Peng Zhao,Kaiyong Cai,Hongwei Cheng
Parkinson's disease (PD), a progressive neurodegenerative disorder, is marked by the degeneration of dopaminergic neurons. Emerging evidence highlights the critical involvement of neuronal ferroptosis and microglial pyroptosis in PD pathogenesis. In this study, we first characterized systemic inflammatory alterations in the peripheral blood of PD patients compared to healthy controls, revealing distinct pro-inflammatory signatures. Based on these findings, we engineered BV2 microglial membrane-camouflaged biomimetic multienzyme gallic acid-selenium nanoparticles (BM@GA-Se nanosomes) and evaluated their neuroprotective potential. In vitro and in vivo experiments demonstrated that BM@GA-Se nanosomes enhanced neuronal survival by simultaneously suppressing ferroptosis of neurons (via GPX4-mediated lipid peroxide reduction) and pyroptosis of microglia (through inhibition of the HSP90/NLRP3/Caspase-1 signaling pathway). These results position BM@GA-Se nanosome as a new dual-pathway targeting therapeutic strategy, offering a promising translational approach to mitigate PD progression by addressing interdependent inflammatory and oxidative mechanisms.
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高影响因子
Journal of Translational Medicine
·
2025
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IF 7.5
Xiaoying Ma,Weibo Shi,Zhen Wang,Shujin Li,Rufei Ma,Weihao Zhu,Lin Wu,Xiaowei Feng,Bin Cong,Yingmin Li
Background Depression is closely associated with stress-induced hippocampal damage and dysfunction. Emerging evidence demonstrates that the gut microbiota and its metabolites, acting as probiotics or prebiotics, can modulate brain structure and function via the gut-brain axis, thereby offering therapeutic potential for ameliorating related neurological and psychiatric disorders. This study delves into the contribution of the gut microbiota and its metabolites to stress-induced ferroptosis of hippocampal neurons and the associated molecular pathways. Methods This study used time-course stress paradigms combined with ferroptosis inhibitors to identify hippocampal neuronal ferroptosis. Fecal microbiota transplantation were conducted to analyze the role of gut microbiota in this process. Subsequently, 16 S rDNA sequencing and metabolomics techniques were applied to identify key gut microbiota and metabolites. Metabolites intervention were performed to examine their causal relationship with neuronal ferroptosis. Finally, we used histochemical and molecular assays to assess both intestinal and blood-brain barrier integrity as well as inflammation in peripheral blood and hippocampal tissue, along with GPR41/RhoA/Rock1 pathway changes, to preliminarily investigate the molecular mechanisms underlying stress-induced hippocampal neuronal ferroptosis. Results We demonstrated that stress triggered hippocampal neuronal ferroptosis and subsequent depressive-like behaviors in mice. Fecal microbiota transplantation successfully replicated the ferroptosis phenotype. Butyric acid and valeric acid were identified as key metabolites significantly reduced in the serum of acutely and chronically stressed mice, respectively. Intervention with these metabolites markedly alleviated ferroptosis. Furthermore, valerate intervention increased hippocampal GPR41 expression and significantly suppressed the pro-inflammatory RhoA/Rock1 pathway in chronically stressed mice, thereby reducing neuroinflammation and ameliorating neuronal ferroptosis. However, butyrate intervention showed no significant effect on the GPR41/RhoA/Rock1 pathway. Conclusion Stress induces ferroptosis in hippocampal neurons, where reduced abundance of short-chain fatty acid-producing bacteria plays a key role. Key metabolites butyric acid and valeric acid alleviate neuroinflammation to improve ferroptosis via the gut-brain axis in acute and chronic stress, respectively. Specifically, valeric acid exerts neuroprotective effect through the GPR41/RhoA/Rock1 pathway, whereas butyric acid-mediated protection likely operates through alternative mechanisms. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12967-025-06950-0.
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Guanhong Liu,Rongze Tang,Congcong Wang,Dehong Yu,Zhenxin Wang,Haochen Yang,Jia Wei,Shunhua Zhu,Fenglei Gao,Feng Yuan,Bin Pan
Cuproptosis and ferroptosis are difficult to synergize in tumor suppression due to their spatiotemporal asynchrony and mechanistic dispersion. Therefore, we proposed a new paradigm of Ferroptosis-Cuproptosis self-recycling. An iron‑sulfur cluster (Fe-S) metabolic collapse was constructed by hyaluronic acid (HA)-functionalized bimetallic nano-enzymes (HA@CuCo-NC) to initiate this tumoricidal mechanism. HA@CuCo-NC specifically accumulates in osteosarcoma cells through HA-mediated targeting. The multi-enzyme activity triggers a surge of reactive oxygen species (ROS) in the tumor microenvironment, which, along with Co 2+ , induces ferroptosis. This leads to severe mitochondrial damage and glutathione (GSH) depletion, which in turn activates the cuproptosis cascade. Cuproptosis causes Fe-S protein degradation and Fe 2+ release into the labile iron pool (LIP) by inhibiting Fe-S cluster formation and dihydrolipoamide acetyltransferase (DLAT) oligomerization. The released Fe 2+ enhances oxidative stress and promotes membrane disassembly via the Fenton reaction. The two act synergistically to form a dynamic self-reinforcing cycle: Ferroptosis-related mitochondrial damage exacerbates the toxicity of Cu 2+ . Cuproptosis-released Fe 2+ further activates ferroptosis. In vivo experiments demonstrated that HA@CuCo-NC significantly inhibited the growth of osteosarcoma in situ without causing systemic toxicity. This research introduces a novel approach to treating solid tumors by reconstructing the metabolic interaction network of copper and iron.
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高影响因子
Advanced Healthcare Materials
·
2026
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IF 11
Wangjing Lu,Juan Yang,Jinxia Mi,Fazhen Luo,Yufan Guo,Yihong Zhang,Xupeng Zhang,Yan Xie
Hepatocellular carcinoma (HCC) remains a formidable malignancy with limited response to conventional monotherapies, largely due to its complicated pathogenesis and useful cellular defense systems. In this study, we constructed a dual-targeting polymeric micelle (S&A@TPD/HG PMs), co-delivering sorafenib (SOR), and artesunate (ART) to achieve synergistic ferroptosis-based therapy against HCC. The micelle features a hyaluronic acid (HA) shell functionalized with glycyrrhetinic acid (GA) for active dual targeting to CD44 and GA receptors overexpressed on HCC cells; while its triphenylphosphonium (TPP)-decorated inner core facilitates mitochondrial anchoring and co-conveys the drugs, enabling stepwise subcellular targeting. Compared with free drugs or single-drug-loaded micelles, S&A@TPD/HG PMs effectively induced mitochondrial damage by depleting glutathione (GSH), and downregulating GSH peroxidase 4 (GPX4) expression to disrupt the mitochondrial antioxidant defense system, elevating intracellular Fe 2+ to increase reactive oxygen species (ROS) and lipid peroxidation (LPO) production, thereby compromising mitochondrial redox homeostasis and potentiating ferroptosis jointly. This ferroptosis-inducing activity yielded potent in vivo antitumor efficacy in Huh-7 tumor-bearing nude mice, with a tumor inhibition rate of 74.23% and minimal systemic toxicity. Collectively, the organelle-specific targeting combined with co-delivery of synergistic drug pairs represents a promising strategy for combating malignancies and provides a blueprint for the rational design of multifunctional nanosystems.
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高影响因子
GENE
·
2025
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IF 2.4
Jiadi Wang,Zhirui Zhang,Yue Liu,Beiting Zong,Yixuan Lu,Yuhang Li,Jing Yao
Background Dry Eye Disease (DED) is an ocular surface disease characterized by reduced tear secretion, abnormal fluid dynamics, and decreased tear quality, leading to instability of the tear film. It is accompanied by eye discomfort, visual impairment, and ocular surface tissue damage. DED is not only associated with the death of corneal epithelial cells but also involves damage to multiple ocular surface tissues, including the meibomian glands, lacrimal glands, conjunctival cells, and goblet cells. Ferroptosis plays a role in corneal epithelial cell death and keratopathy, but its underlying mechanisms remain unclear and require further investigation. Methods This study utilized the GSE208297 dataset (from the Gene Expression Omnibus, GEO) to analyze the gene expression profiles of Mus musculus with DED. Five untreated DED samples and five normal control samples were selected for differential gene expression analysis to identify ferroptosis-related differentially expressed genes (FRDEGs). Based on these FRDEGs, comparative gene expression analysis, functional enrichment analysis, and small-molecule interaction network analysis were conducted. Additionally, gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed, and immune infiltration analysis was conducted. A rat model of DED was induced using benzalkonium chloride (Benzalkonium chloride, 0.2 % solution, 5 µl, twice daily for 15 days). The tear secretion was assessed by the Schirmer I test, and structural changes in corneal tissue were observed by hematoxylin and eosin (HE) staining. Mitochondrial changes were examined by transmission electron microscopy (TEM), and ferroptosis was confirmed using malondialdehyde (MDA) and glutathione (GSH) kits. RT-PCR was used for the validation of gene expression analysis, confirming the mRNA expression changes of 8 key genes in the corneal tissue of DED rats. Results Differential gene expression analysis identified 136 genes with abnormal expression. After intersecting these genes with 833 known ferroptosis-related genes, 13 FRDEGs were identified. These genes were primarily enriched in functions related to muscle tissue development, regulation of white blood cell differentiation, positive regulation of apoptosis signaling pathways, and inflammatory response regulation, as well as KEGG pathways such as MAPK, TNF, and IL-17 signaling. Immune cell infiltration analysis revealed significant differences in immune cell infiltration between DED and control groups, with CD8 T cells, macrophages, and NK cells showing correlations with the expression of FRDEGs. In the small-molecule interaction network analysis, eight key genes (ARNTL, ATF3, CCL5, JUN, KRT14, MYC, NR4A1, and TNF) exhibited strong interaction relationships with other small molecules. RT-PCR verification confirmed significant mRNA expression changes of these eight key genes in the corneal tissue of DED rats. MDA and GSH experiments further confirmed the ferroptosis phenotype in the corneas of DED rats, and TEM and HE staining showed corneal epithelial damage and mitochondrial cristae reduction. Conclusions Ferroptosis plays a key role in corneal cell death and keratopathy, amplifying inflammatory responses and contributing to the pathogenesis of DED. This study provides new molecular targets for therapeutic interventions in DED and reveals the potential mechanisms of ferroptosis in immune responses.
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高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2026
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IF 19.9
Tianxing Zhou,Junnian Chen,Xingya Rao,Haifeng Zhang,Huocheng Yang,Menghuan Li,Zhong Luo
Triple-negative breast cancer (TNBC) is a highly invasive malignancy that responds poorly to current standard therapies. Sonodynamic therapy (SDT) can deliver both reactive oxygen species (ROS)-dependent tumor cytotoxicity and immunostimulatory benefits that holds significant promise for TNBC treatment, but its efficacy is blunted by the elevated Indoleamine 2,3-dioxygenase 1 (IDO1)-driven tryptophan (Trp) catabolism in TNBC, which strengthens antioxidant defenses while exacerbating the immunosuppressive tumor microenvironment. Here we develop an ultrasound-activatable sonodynamic amplifier (PMFN) that reprograms TNBC-intrinsic IDO1-dependent Trp catabolism to potentiate remotely controllable sonodynamic ferroptosis-immunotherapy. We first developed Fe(III)-coordinated tetraphenylporphyrin (FeTPP) as a ferrocatalytic sonosensitizer via molecular-dynamics-assisted virtual screening, which was co-formulated with the IDO1 inhibitor Navoximod (NLG919) into cRGD-modified liposomes for TNBC-targeted delivery. Upon ultrasonication, NLG919 blocks Trp-to-kynurenine (Kyn) conversion to suppress the Nrf2-GPX4 antioxidant axis and mitigate regulatory T cells (Tregs)-associated immunosuppression, while FeTPP amplifies ROS stress through a sonodynamic reaction to drive lipid peroxidation. These effects synergistically promoted immunogenic ferroptosis of TNBC cells and relieved immune suppression, thereby enhancing ferroptosis-immunotherapeutic efficacy. In mouse models, PMFN markedly inhibited primary TNBC growth and abrogated metastasis, providing an approach for advancing TNBC treatment in the clinic.
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高影响因子
Materials Today Bio
·
2026
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IF 11
Qiang Zhou,Xiaolong Xu,Shuyi Lin,Yida Wang,Yuqi Han,Wenxin Liang,Ran Mo,Xianlong Wang,Yiyang Cheng,Chengxuan Tang,Lingxiao Zhang,Yiheng Yang,Xianzhen Chen,Liangle Liu
Facial nerve injury (FNI) is a common form of peripheral nerve damage that often results in incomplete functional recovery due to a hostile microenvironment characterized by excessive oxidative stress and inflammatory activation. These pathological conditions disrupt Schwann cell homeostasis, impair myelin maintenance, and hinder nerve regeneration. Although ferroptosis, an iron-dependent lipid peroxidation-driven form of regulated cell death, has been implicated in peripheral nerve disorders, its involvement in acute FNI remains not fully defined. In this study, transcriptomic analysis of injured facial nerve tissue suggested ferroptosis-related transcriptional alterations and lipid peroxidation-associated cellular injury during the acute phase of FNI, including changes in ferroptosis-related gene expression, decreased GPX4 levels, and increased 4-HNE accumulation. To modulate this complex microenvironment, we developed a peripheral nerve-targeted, ROS-responsive liposomal nanoplatform (F-MHC@PNRLs) co-delivering Ferrostatin-1 (Fer-1) and Mn-doped CeO 2 nanozymes (MHC). The designed system integrates complementary mechanisms, where MHC provides catalytic ROS-scavenging activity to regulate upstream oxidative stress, while Fer-1 acts downstream to suppress lipid peroxidation propagation. In addition, NP41 peptide modification enhances peripheral nerve-associated retention and lesion-site accumulation following local administration. In a mouse FNI model, F-MHC@PNRLs effectively reduced oxidative stress, modulated macrophage polarization toward a reparative phenotype, and was associated with activation of NRF2/HO-1 antioxidant signaling while inhibiting NF-κB/MAPK-mediated inflammatory responses. Furthermore, F-MHC@PNRLs alleviated Schwann cell injury, preserved mitochondrial homeostasis, and promoted remyelination, leading to improved functional and electrophysiological recovery. Importantly, the formulation exhibited favorable preliminary biosafety in vivo. Collectively, these findings suggest that ferroptosis-related lipid peroxidation and oxidative inflammatory imbalance are involved in acute FNI pathology, and demonstrate that NP41-modified ROS-responsive liposomes co-delivering Fer-1 and Mn-doped CeO 2 nanozymes represent a promising strategy for enhancing facial nerve repair.
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PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2026
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IF 4.3
Leilei Qin,Yanli Guo,Yi Zhang,Nianting Tong,Chunning Zhao
Ribosomal L1 domain-containing protein 1 (RSL1D1) is an RNA-binding protein that relates to senescence. Nevertheless, the mechanism of RSL1D1 in modulating senescence and ferroptosis in diabetic retinopathy (DR) remains undefined. The DR mice were developed by intraperitoneal injection of STZ, and AAV targeting RPE was used for gene intervention. ARPE-19 cells were infected using oe-RSL1D1 and sh-FTH1 lentivirus before 30 mM high glucose (HG) exposure. Cell damage was assessed by measuring the expression of senescence and ferroptosis markers in ARPE-19 cells, along with oxidative stress indicators and Fe 2+ levels. RSL1D1 and FTH1 expression were significantly reduced in the retinal pigment epithelium (RPE) layer of diabetic mice and HG-induced ARPE-19 cells. Downregulation of RSL1D1 led to RPE cell senescence and dysregulated iron homeostasis-induced ferroptosis. HG treatment reduced the interaction between RSL1D1 protein and FTH1 mRNA in ARPE-19 cells, while RSL1D1 overexpression enhanced this interaction, thereby stabilizing FTH1 mRNA expression. The alleviating effects of RSL1D1 overexpression on retinal pigment epithelium cell senescence and ferroptosis in vitro and in vivo were compromised by FTH1 knockdown. Overall, this study unveils a posttranscriptional regulation of FTH1 by RSL1D1 and uncovers the implication of RSL1D1/FTH1 in cellular senescence and ferroptosis in DR.
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高影响因子
PHYTOMEDICINE
·
2026
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IF 11.3
Wei Ye,Ze Lin,Zihan You,Zijian Zhu,Zhengzhong Yuan
Background Jiao-tai-wan (JTW) is a classic formula for Heart-Kidney Disharmony insomnia, yet its mechanism in hippocampal neurons remains unclear. Purpose To investigate whether JTW ameliorates insomnia-induced hippocampal neuronal damage by inhibiting ferroptosis and elucidate the underlying mechanisms. Methods UPLC-Q-TOF/MS analyzed JTW constituents. Network pharmacology and molecular docking predicted core targets. A mouse insomnia model was established using PCPA combined with MMPM. Behavioral tests, pathological examinations, and ferroptosis markers were evaluated. In vitro, HT22 cells underwent IKE-induced ferroptosis to validate Jiao-tai-wan drug-containing serum (JTWS) and the PDE4D inhibitor Zatolmilast (ZAT). Results 413 compounds were identified in JTW, with 47 predicted to penetrate the blood-brain barrier. Network pharmacology, molecular docking, and molecular dynamics simulations predicted PDE4D and BDNF as core targets. In vivo, JTW ameliorated cognitive deficits, attenuated hippocampal neuronal damage, and restored mitochondrial ultrastructure. Mechanistically, JTW downregulated Ptgs2 expression, upregulated Gpx4, Fth1, and Acsl3 expression, reduced lipid peroxidation and iron accumulation, while simultaneously suppressing Pde4d and restoring Bdnf levels. In vitro, ZAT mimicked the anti-ferroptotic effects of JTW. Conclusion JTW inhibits hippocampal neuronal ferroptosis through multi-target regulation, ameliorating insomnia-related neuronal damage and providing a molecular basis for its traditional efficacy in restoring Heart-Kidney communication. Download: Download high-res image (282KB) Download: Download full-size image
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危险品化学品经营许可证（带存储）