JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2026
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IF 9.7
Zhuanxia He,Limin Zhang,Xiujun Gao,Jiaxin Zhong,Yanqi Zhang,Feng Gao
Phototheranostics have emerged as a promising approach in precision medicine. However, the poor tumor selectivity of photosensitizers, insufficient oxidative stress and the intrinsic antioxidant system of tumors compromise the efficacy of phototherapeutic strategies. In this study, we designed a novel phototheranostic platform (ICP@SRF-GPC3 NPs) for active tumor-targeted imaging and oxidation-enhanced photoimmunotherapy-ferroptosis combined therapy. The ICP@SRF-GPC3 NPs were fabricated by conjugating near-infrared photosensitizer IR780 with cystine-polyethylene glycol, modifying it with the Glypican-3 monoclonal antibody and encapsulating of the ferroptosis inducer sorafenib (SRF). ICP@SRF-GPC3 NPs with improved water solubility and liver tumor specificity can produce reactive oxygen species (ROS) upon 808 nm laser irradiation and enable photoimmunotherapy-mediated oxidation treatment. In the tumor microenvironment, the high concentration of glutathione (GSH) cleaved the linkage between the IR780 and the cystine moiety, realizing superior near-infrared fluorescence imaging and synergistic photoimmunotherapy-ferroptosis therapy. The released SRF inhibited cystine/glutamate antiporter, thereby blocking cystine uptake in tumor cells and suppressing GSH synthesis. By depleting existing GSH reserves while simultaneously inhibiting its biosynthetic pathway, ICP@SRF-GPC3 NPs effectively exhausted intracellular GSH, weakening the anti-oxidation ability of tumor cells and amplifying oxidative stress. In a BALB/c nude mouse model bearing GPC3-overexpressing Hepa1–6 allografts, the combination of photoimmunotherapy with ferroptosis not only effectively suppressed primary tumor growth through amplified ROS generation, but also promoted damage-associated molecular patterns release, thereby eliciting a robust immune response that eliminated metastatic and distant tumors. Overall, ICP@SRF-GPC3 NPs offers a promising strategy for regulating GSH and ROS levels in synergistic photoimmunotherapy-ferroptosis antitumor therapy, which has potential clinical applications.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2026
·Vol. 1872
·期 4
·168154
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IF 4.2
Mengli Tao,Jiayi Shi,Yingying Zhang,Yigang Zheng,Yufen Zhao,Huabin Ma,Long Li
Objective Acetaminophen (APAP)-induced liver injury (ALI), the major cause of acute drug-induced hepatotoxicity, lacks effective therapies. Berbamine (BBM), a bisbenzylisoquinoline alkaloid derived from the genus Berberis , exhibits diverse pharmacological properties but its efficacy against ALI and involvement in ferroptosis remains unexplored. This study aims to investigate the hepatoprotective effects and mechanisms of BBM against ALI and ferroptosis. Methods The in vivo model of ALI and the in vitro ferroptosis models were established using APAP and RSL3, respectively. Models received BBM or Ferrostatin-1 (Fer-1) treatment. The direct target of BBM was identified through molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays. Results In vivo, BBM pretreatment dose-dependently alleviated APAP-induced hepatic damage, inflammation, and ferroptosis markers, including lipid peroxidation, GSH depletion, and PTGS2 upregulation, while upregulating GPX4. Meanwhile, the hepatoprotective effects of BBM against ALI matched Fer-1, confirming ferroptosis as an ALI driver. In vitro, BBM inhibited RSL3-induced ferroptosis, reducing ROS, lipid peroxidation, and mitochondrial dysfunction. These effects were mediated by NRF2/GCLC/GPX4 axis activation and FSP1 upregulation. Crucially, BBM directly bound GCLC confirmed by Molecular docking, CETSA, and DARTS. Conclusion BBM protects against ALI by mitigating ferroptosis, oxidative stress, and inflammation, in part through direct modulation of GCLC and coordinated activation of the NRF2/GCLC/GPX4 axis together with FSP1. These findings provide pharmacological evidence supporting the potential of BBM as a promising therapeutic candidate for ALI.
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EXPERIMENTAL AND MOLECULAR MEDICINE
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2026
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IF 12.9
Chen Fan-feng,Zhang Yin-he,Wu Zi-chang,Du Kaiyi,Chen Xinyuan,Lu Yang,Hu Qianqian,Du Anyu,Du Shenghu,Wang Jian,Shi Keqing,Chen Zimiao,He Zili,Zhou Kailiang,Xiao Jian
Acute limb ischemia–reperfusion injury (ALIRI) prominently involves microvascular dysfunction, with notable contributions from damage to microvascular endothelial cells (MECs). Previous research suggests that the mechanosensitive ion channel Piezo1 becomes active in response to mechanical stress conditions, including ischemia and trauma. However, its precise function within the ALIRI context remains elusive. Notably, the expression of Piezo1 was markedly elevated postreperfusion in mouse hind limb ischemia/reperfusion (I/R) models, implicating its crucial involvement in limb survival. Employing specific inhibitors of cell death pathways, the study delineated key molecular drivers of ferroptosis during limb damage. Here evaluations of limb vitality, western blot, quantitative PCR and immunofluorescence implicated that activation of Piezo1 by its agonist exacerbates I/R-induced microvascular perfusion deficits, tissue swelling, skeletal muscle damage and increased tissue infarction and MECs damage. Conversely, these detrimental impacts were mitigated through pharmacological blockade of Piezo1 or specific deletion of Piezo1 in MECs. Comprehensive untargeted metabolomic analysis revealed significant changes primarily in glycerophospholipid and arachidonic acid metabolism pathways. Further experiments demonstrated that RNA interference-mediated inhibition of cytosolic phospholipase A2 (cPLA2) and acyl-CoA synthetase long-chain family member 4 (ACSL4) negated the protective effects against ferroptosis and limb damage that were observed with Piezo1 deletion. Moreover, this study confirmed that protein kinase C phosphorylates ACSL4, which mediates Piezo1-induced ferroptosis and exacerbates limb damage, as shown through immunoprecipitation studies. In summary, Piezo1 contributes to the exacerbation of microvascular and skeletal muscle damage in ALIRI by facilitating the cPLA2-dependent release of arachidonic acid and promoting ACSL4-driven lipid peroxidation, thereby intensifying ferroptosis in MECs.
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BRITISH JOURNAL OF PHARMACOLOGY
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2026
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IF 7.5
Chang Liu,Zhuoqun Wang,Linxin Zhang,Di Yang,Zhihong Zhang,Xiaoli Cui,Ali H. Eid,Mengyang Wang
Background and Purpose Fangchinoline (FAN), a bioactive bisbenzylisoquinoline alkaloid from Stephania tetrandra , shows protective potential against angiotensin II (Ang II)-induced hypertensive heart failure (HF), particularly involving mitophagy and ferroptosis, remain unclear. We investigated the effects of FAN on Ang II-induced cardiac remodelling and HF. Experimental Approach A hypertensive heart failure model was established in C57BL/6 mice via 4-week Ang II infusion. FAN was administered during the final 2 weeks. Cardiac function was assessed by echocardiography and pathological remodelling was evaluated by histological staining. RNA sequencing of cardiac tissue was performed to investigate the mechanism of anti-heart failure action of FAN. The potential binding proteins of FAN were verified by molecular docking, drug affinity response target stability (DARTS), cellular thermal shift assay (CETSA) and surface plasmon resonance assay (SPR). In vitro , neonatal rat ventricular myocytes (NRVMs) were used to investigate the effects of FAN on cellular hypertrophy, mitophagy and ferroptosis. Key Results In vivo , FAN treatment significantly ameliorated cardiac hypertrophy, dysfunction and fibrosis. These protective effects were independent of blood pressure-lowering actions. Mechanistically, FAN activates PGC-1α to enhance mitophagy and suppress STAT6-PPARγ signalling, thereby inhibiting ferroptosis and restoring redox homeostasis. In vitro , FAN reduced Ang II-induced NRVM hypertrophy, ROS production and mitochondrial membrane potential depolarisation, and confirmed the modulation of mitophagy and ferroptosis markers. Conclusions and Implications We demonstrate that FAN alleviates Ang II-induced HF through a mechanism involving the activation of PGC-1α-mediated mitophagy and regulation of the STAT6-PPARγ pathway, ultimately suppressing cardiomyocyte ferroptosis. These results offer new perspectives for HF treatment. Graphical FAN mitigates HF by engaging PGC-1α-mediated mitophagy and STAT6-PPARγ to counteract ferroptosis.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Luyao Xu,Jing Feng,Shihao Xu,Mingli Jin,Xianyue Bai,Hui Zhang,Minghui Zhu,Shengmin Lin,Jiaxing Song,Cuixia Lu
Multimodal targeted combination therapy that harnesses synergistic effects has emerged as a transformative paradigm in cancer therapy, progressively replacing traditional monotherapy. Herein, we report a tumor microenvironment (TME)-responsive multifunctional nanoplatform Cu-Ce6@DHA NPs (CCD NPs), which is self-assembled through the coordination of Cu²⁺, the antitumor drug dihydroartemisinin (DHA), and the photosensitizer chlorin e6 (Ce6). This nanoplatform enables the near-infrared-triggered combination of cuproptosis and ferroptosis for tumor treatment. Upon internalization by tumor cells, these nanoparticles undergo glutathione (GSH)-triggered disintegration, releasing their encapsulated payloads within the TME. The released Ce6 mediates potent photodynamic therapy (PDT) under laser irradiation, and DHA undergoes GSH-dependent activation to generate cytotoxic reactive oxygen species (ROS) and suppresses glutathione peroxidase 4 (GPX4), thereby amplifying ferroptotic cell death. Concurrently, the released copper ions deplete intracellular GSH and further inhibit GPX4, which exacerbates lipid peroxidation and promotes ferroptosis. Notably, the intracellular accumulation of copper ions disrupts mitochondrial metabolism by destabilizing iron-sulfur cluster (Fe-S) proteins and inducing oligomerization of lipoylated lipoylated dihydrolipoamide S-acetyltransferase (DLAT), ultimately triggering cuproptosis. Therefore, our findings establish a novel nanoplatform that simultaneously exploits metabolic vulnerabilities (via cuproptosis), redox imbalances (via ferroptosis), and photodynamic effects, providing a promising multimodal therapeutic strategy for cancer treatment.
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Scientific Reports
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2025
·Vol. 15
·期 1
·1-17
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IF 3.9
Chen Dongzhui,Yin Feifei,Yang Pin,Xia Wanrong,Huang Yi,Feng Yue,Yang Li,Lin Shuqiang,Zhang Qiuyue
Bronchopulmonary dysplasia (BPD) is one of the most common respiratory diseases in preterm infants. Studies have shown that ferroptosis is involved in the pathogenesis of BPD, and thioredoxin-interacting protein (TXNIP)-mediated oxidative stress also plays a role in its development. The solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway is one of the key pathways regulating ferroptosis. This study aimed to investigate the mechanism by which TXNIP regulates SLC7A11/GPX4 pathway-mediated ferroptosis in BPD. Mice were randomly divided into ten treatment groups: Air, Hyperoxia, Hyperoxia + RSL3, Hyperoxia + Ferrostatin-1, Hyperoxia + Ad-shNC, Hyperoxia + Ad-shTXNIP, Hyperoxia + Ad-vector, Hyperoxia + Ad-TXNIP, Hyperoxia + Ad-shSLC7A11, and Hyperoxia + Ad-shTXNIP + Ad-shSLC7A11. Lung tissues were collected for hematoxylin and eosin (H&E) staining to observe pathological changes, and transmission electron microscopy (TEM) was used to examine mitochondrial morphology. Real-time quantitative polymerase chain reaction (qPCR) was performed to measure the mRNA expression of TXNIP, SLC7A11, and GPX4. Western blotting was used to analyze the protein levels of TXNIP, SLC7A11, and GPX4. GPX4 activity was determined using an enzyme-linked immunosorbent assay (ELISA). Additionally, glutathione (GSH), malondialdehyde (MDA), and ferrous iron (Fe 2+ ) levels in lung tissues were measured using corresponding detection kits. H&E staining and TEM confirmed successful modeling of lung injury after hyperoxia. MDA and Fe 2+ increased, GSH decreased, and GPX4 activity declined after hyperoxia. TXNIP mRNA and protein were upregulated by hyperoxia, while SLC7A11 and GPX4 were downregulated. Ferroptosis activation exacerbated lung injury, whereas inhibition alleviated it. TXNIP overexpression using adenovirus serotype 5 (Ad5) aggravated ferroptosis in BPD, and this was ameliorated by TXNIP knockdown. Knockdown of the upstream signal SLC7A11 increased ferroptosis in BPD, and simultaneous knockdown of TXNIP and SLC7A11 reversed the ferroptosis reduction. In conclusion, in the BPD model, TXNIP expression was increased, and TXNIP promoted ferroptosis by downregulating the SLC7A11/GPX4 pathway. These findings suggest that gene therapy targeting TXNIP knockdown using adenovirus as a vector may serve as a therapeutic strategy for BPD.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·Vol. 24
·期 1
·301
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IF 15
Yin Mingming,Wang Bing-Hao,Wang Huijuan,Ouyang Jie,Hu Xingsheng,Wang Xiong,Liu Yongping,Xu Fenghua,Chen Yi,Yin Shuang-Feng
Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with limited therapeutic options and poor prognosis. Although single-atom nanozymes (SAzymes) show promise in cancer therapy, their ferroptosis-inducing capability remains limited. Herein, we present a rationally designed iron-based SAzyme with axial chlorine coordination (FeN 4 Cl) that integrates catalytic and metabolic functions to enhance ferroptosis in TNBC. The engineered Fe-Cl coordination strategically modulates the d-band center relative to the Fermi level, resulting in significantly enhanced peroxidase-like activity (2.0-fold increase) and glutathione oxidase-like activity (3.2-fold increase) activities compared to conventional FeN 4 structures. Importantly, this electronic modulation triggers NCOA4-mediated ferritinophagy, establishing an autonomous iron supply mechanism that elevates intracellular labile Fe 2+ levels. The synergistic disruption of redox homeostasis coupled with amplified Fenton reactions creates a feedback loop that induces cell death. Encapsulation within red blood cell membranes (FeN 4 Cl/RBC) improves biocompatibility and tumor targeting. Both in vitro and in vivo studies demonstrate that FeN 4 Cl/RBC substantially suppresses tumor growth through effective ferroptosis, presenting a promising approach for developing clinically relevant nanozyme-based therapeutics. Graphical The alternative text for this image may have been generated using AI.
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JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Xinmei Wang,Shanshan Li,Jiayu Yu,Wenlin Wang,Zhuoqi Du,Shuchun Gao,Yin Ma,Ruixin Tang,Ting Liu,Shiping Ma,Qiang Fu,Xueyang Deng
s Ethnopharmacological relevance Saikosaponins B2 (SSB2) is one of the main active components isolated from Radix Bupleuri (Bupleurum chinense DC.), a herb widely used of traditional Chinese medicine. It has been used for the treatment of depression for more than two thousand years. However, the molecular mechanisms remain to be determined. Aim of the study In this study, we evaluated the anti-inflammatory effect and elucidated underlying molecular mechanisms of SSB2 in LPS-induced primary microglia and CUMS-induced mice model of depression. Method The effects of SSB2 treatment were investigated both in vitro and in vivo. The chronic unpredictable mild stimulation (CUMS) procedure was applied to establish the animal model of depression. Behavioural tests were used to evaluate the depressive-like behaviors in CUMS-exposed mice, including sucrose preference test, open field test, tail suspension test, and forced swimming test. The GPX4 gene of microglia was silenced using shRNA, and inflammatory cytokines were determined by Western Blot and immunofluorescence analysis. Endoplasmic reticulum stress and ferroptosis-related markers were detected by qPCR, flow cytometry and confocal microscopy. Result SSB2 reversed depressive-like behaviours in CUMS-exposed mice and relieved central neuroinflammation and ameliorated hippocampal neural damage. SSB2 alleviated LPS-induced activation of microglia through the TLR4/NF-κB pathway. LPS-induced ferroptosis, with increased levels of ROS, intracellular Fe 2+ , mitochondrial membrane potential, lipid peroxidation, GSH, SLC7A11, FTH, GPX4 and Nrf2, and decreased transcription levels of ACSL4 and TFR1, was attenuated with SSB2 treatment in primary microglia cells. GPX4 knockdown activated ferroptosis, induced endoplasmic reticulum (ER) stress, and abrogated the protective effects of SSB2. Further, SSB2 attenuated ER stress, balanced calcium homeostasis, reduced lipid peroxidation and intracellular Fe 2+ content by regulating the level of intracellular Ca 2+ . Conclusions Our study suggested that SSB2 treatment can inhibit ferroptosis, maintain calcium homeostasis, relieve endoplasmic reticulum stress and attenuate central neuroinflammation. SSB2 exhibited anti-ferroptosis and anti-neuroinflammatory effects through the TLR4/NF-κB pathway in a GPX4-dependent manner.
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CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Qiwen Pan,Fei Lin,Ruiqi Liu,Yilin Li,Xinyue Zhang,Rui Luo,Lingling Cai,Yang Liu,Wuguo Deng,Liru He
Nanocatalysts provide a platform for developing anti-tumor strategies by activating intratumoral chemical catalysis to produce highly toxic reactive oxygen species (ROS). However, the biological effect of nanocatalysts on tumor cells, which is pivotal for effective nanotherapy treatment, remains poorly understood. Herein, we present a general and facile method of synthesizing Fe/Ni-layered double hydroxides (LDHs) for enhanced apoptosis- and ferroptosis-induced cancer nano-therapy, as well as a potential mechanism underlying the anti-tumor effect based on transcriptome sequencing. An analysis of the chemical structure suggests that the Fe atoms interact strongly with the Ni atoms in Fe/Ni-LDH. Compared with Fe-OH and Ni-OH, Fe/Ni-LDH exhibited significantly better ROS-catalytic activity, with a V max of 5.015 × 10 −2 μM·s −1 , and generated massive amounts of •OH and O 2 •− radicals, enabling outstanding chemo-dynamic therapy. Both in vitro and in vivo experiments indicated a robust apoptosis-induced cell death pathway, increased intracellular oxidative stress, and accumulation of lipid peroxide (LPO), promoting ferroptosis-involved cancer-cell death, which was further confirmed by transcriptome sequencing. The Fe/Ni-LDH biocatalyst not only provides a robust nanoplatform for tumor suppression but also encourages further exploration and applications of nanobiocatalysts.
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Materials Today Chemistry
·
2022
·
IF 7.613
T. Fang,S. Ma,Y. Wei,J. Yang,J. Zhang,Q. Shen
Tumor cell vaccine is a promising approach for cancer therapy to activate tumor immune, which can be achieved by tumor cells immunogenic cell death (ICD), converting in situ tumors into endogenous vaccination strategy, and ferroptosis has been proved to induce ICD occurrence. Ferroptosis is triggered by artificial nanoenzyme copper telluride mimicking peroxidase and glutathione oxidase, based on which the ferroptosis-activating vaccine (termed as CM [email protected] ) was designed and established for catalytic immunotherapy. Owing to photothermal effect of copper telluride, photothermal therapy (PTT) was combined for an intensive cancer therapeutic effect. CM [email protected] was composed of solid mesoporous copper telluride nanoparticles , ovalbumin (OVA) loaded in mesoporous, and melanoma cell membrane coating surface . In in vitro and in vivo investigations, CM [email protected] , with particle size of 113.7 ± 1.7 nm, was certified to release copper ions for ferroptosis initiation, and OVA directly maturated dendritic cell (DC) as exogenous antigens extracellularly. ICD was then induced by ferroptosis pathway and PTT to release damage-associated molecular patterns for DC maturation and subsequent T cells recruitment. CM [email protected] melanoma with exited inhibition rate, proving that the strategy of catalytic immunotherapy-PTT combination by ferroptosis-activating vaccine possessed massive potential for melanoma therapy based on nanoenzyme copper telluride.
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CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Shuxiang Xu,Shuyi Zhou,Luoyijun Xie,Wenlong Dou,Rongjun Zhang,Bingxia Zhao,Yang Xu,Xuemei Fu,Miaomiao Yuan
Due to the heterogeneous and complex tumor microenvironment (TME), it remains challenging to effectively treat solid tumors with monotherapy. The development of a versatile nanomaterial strategy for synergistic chemodynamic/photodynamic/photothermal therapies has the potential to overcome this challenge. Herein, we designed and synthesized NiS 2 /FeS 2 hybrid nanoparticles (NiS 2 /FeS 2 NPs), which are further modified with polyvinyl pyrrolidone (PVP) to improve their biocompatibility. PVP-NiS 2 /FeS 2 NPs exhibit synergistic activities of chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) with multimodal imaging capabilities. With the presence of Fe 2+ /Fe 3+ and Ni 2+ /Ni 3+ redox couples, the PVP-NiS 2 /FeS 2 NPs exhibit GSH peroxidase-like reactivity and trigger Fenton reaction, leading to robust ·OH generation and pyroptosis/ferroptosis after near infared irradiation (NIR). In response to the PVP-NiS 2 /FeS 2 NPs and PVP-NiS 2 /FeS 2 NPs + NIR treatment, the breast tumors formed in the syngeneic BABL/c mice were eliminated and their metastases suppressed by inhibiting the EMT pathway. Consistent with the apparent involvement of these programmed cell death pathways in activating tumor immunity, we demonstrate that PVP-NiS 2 /FeS 2 NPs + NIR can eliminate metastatic tumors in an immune system dependent manner. Therefore, PVP-NiS 2 /FeS 2 NPs represent a promising strategy to treat metastatic breast cancer.
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Redox Biology
·
2022
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IF 10.787
Yi Zhao,Hao Zhang,Jia-Gen Cui,Jia-Xin Wang,Ming-Shan Chen,Hao-Ran Wang,Xue-Nan Li,Jin-Long Li
The global rate of human male infertility is rising at an alarming rate owing to environmental and lifestyle changes. Phthalates are the most hazardous chemical additives in plastics and have an apparently negative impact on the function of male reproductive system. Ferroptosis is a recently described form of iron-dependent cell death and has been linked to several diseases. Transferrin receptor (TfRC), a specific ferroptosis marker, is a universal iron importer for all cells using extracellular transferrin. We aim to investigate the potential involvement of ferroptosis during male reproductive toxicity, and provide means for drawing conclusions on the effect of ferroptosis in phthalates-induced male reproductive disease. In this study, we found that di (2-ethylhexyl) phthalate (DEHP) triggered blood-testis barrier (BTB) dysfunction in the mouse testicular tissues. DEHP also induced mitochondrial morphological changes and lipid peroxidation, which are manifestations of ferroptosis. As the primary metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP) induced ferroptosis by inhibiting glutathione defense network and increasing lipid peroxidation. TfRC knockdown blocked MEHP-induced ferroptosis by decreasing mitochondrial and intracellular levels of Fe 2+ . Our findings indicate that TfRC can regulate Sertoli cell ferroptosis and therefore is a novel therapeutic molecule for reproductive disorders in male patients with infertility.
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