INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Juan Wang,Junyu Wang,Jun Zhang,Haoran Ye,Dawei Wang,Ling Tao,Yongchao Yao,Ying Chen,Xiangchun Shen
As a notoriously incurable tumor, triple-negative breast cancer (TNBC) exhibits significant sensitivity to ferroptosis and the glutathione (GSH) antioxidant defense system plays a crucial role in its progression. Herein, we report a bimetallic chitosan/hyaluronic acid nanoparticle (5FCN, with a Fe/Cu mass ratio of 5:5) that employs a self-amplified dual mechanism of ferroptosis and cuproptosis for TNBC therapy. Hyaluronic acid in 5FCN specifically binds to the overexpressed CD44 receptor on TNBC cells. This allows 5FCN to enter cells via receptor-mediated endocytosis, then release metal ions in acidic environments. Released Fe 3+ and Cu 2+ react with GSH in tumor cells, weakening the antioxidant system and producing Fe 2+ and Cu + . These ions trigger Fenton/Fenton-like reactions with H 2 O 2 , generating toxic hydroxyl radicals (·OH) to boost ferroptosis. Meanwhile, high-valent Cu 2+ and Fe 3+ are produced, forming a cycle for GSH depletion and ·OH generation. As H 2 O 2 depletes, the rising Cu + level in cells causes lipoylated protein aggregation, amplifying cuproptosis. In vitro and in vivo studies demonstrated that 5FCN exhibited superior cell-killing efficacy against TNBC with few side effects. Collectively, 5FCN represents a potential drug to self-amplify ferroptosis/cuproptosis in TNBC.
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CANCER CHEMOTHERAPY AND PHARMACOLOGY
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2024
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IF 2.7
Ma Xuan,Sun Zhenou,Chen Hui,Cao Lixing,Zhao Shuang,Fan Lihong,Zhao Chong,Yin Shutao,Hu Hongbo
Purpose 18β-glycyrrhetinic acid (GA), the main metabolite of glycyrrhizic acid extracted from the root of licorice, has been reported to possess anti-cancer and immunomodulatory activity, but the mechanisms are not well understood. Recent studies have shown that ferroptosis of immune cells is involved in tumor-associated immune suppression. The purpose of this study was to investigate whether the enhanced immune response via inhibiting immune cell ferroptosis contributed to the anticancer effect of 18β-GA. Methods Lewis Lung carcinoma mouse model and Murine CD8 + T cell culture model were used to examine the changes of immune response and ferroptosis of immune cells. Results We found that 18β-GA was effective against lung cancer accompanied by enhanced activation of tumor-infiltrating CD8 + T cells in Lewis Lung carcinoma mouse model. Furthermore, we demonstrated that the boosted immune response by GA was attributed to its ability to inhibit arachidonic acid (AA)-mediated CD8 + T ferroptosis via suppressing CD36 expression. Conclusion The findings of the present study unraveled a novel mechanism underlying the anti-cancer and immunomodulatory activity of 18β-GA and support that 18β-GA holds potential to be used as an immune enhancer for lung cancer prevention or treatment.
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Xuerong Zhao,Zhuoya Wang,Guanlin Wu,Lianhong Yin,Lina Xu,Ning Wang,Jinyong Peng
Intestinal ischemia reperfusion injury (II/R injury) is a common and intractable pathophysiological process in critical patients, for which exploring new treatments and mechanisms is of great importance to improve treatment outcomes. Apigenin-7-O-Glucoside (AGL) is a sugar derivative of apigenin natural product with various pharmacological activities to protect against intestinal diseases . In this study, we synthesized two amphiphilic molecules, namely DTPA-N10–10 and mPEG-TK-DA, which can scavenge free radicals and reactive oxygen species (ROS). They were successfully encapsulated AGL through self-assembly, resulting in the formation of multi-site ROS scavenging nanoparticles called PDN@AGL. In vitro and in vivo experiments demonstrated that PDN@AGL could protect intestinal tissues by reducing lipid peroxidation, lowering ROS levels and inhibiting ferroptosis during II/R injury. Furthermore, our study revealed, for the first time, that the regulation of the ATF3/SLC7A11 pathway by PDN@AGL may play a crucial role in mitigating II/R injury. In conclusion, our study confirmed the beneficial effects of PDN@AGL in combating II/R injury through the ATF3/SLC7A11-mediated regulation of ferroptosis and oxidative stress. These findings lay the groundwork for the potential application of PDN@AGL in the treatment of II/R injury.
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Theranostics
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2024
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IF 12.4
Wenwen Yang,Yueqi Wang,Changgeng Fu,Changjian Li,Feng Feng,Hongzheng Li,Ling Tan,Hua Qu,Hui Hui,Jingjing Wang,Jie Tian,Linzi Long
Myocardial ischemia-reperfusion (MI/R) injury is a complication in vascular reperfusion therapy for MI, occurring in approximately 60% of patients. Ferroptosis is an important process in the development of MI/R cardiac lesions. Transferrin receptor 1 (TfR1), a marker of ferroptosis, corresponds to the changes in MI/R cardiac lesions and is expected to be a biomarker for detecting MI/R-induced ferroptosis. However, the noninvasive in vivo visualization of ferroptosis in MI/R is a big challenge. Thus, this study aimed to develop a novel multimodal imaging platform to identify markers of MI/R cardiac lesions in vivo through targeting TfR1. Methods: Magnetic particle imaging (MPI) modality for ferroptosis based on superparamagnetic cubic-iron oxide nanoparticles (SCIO NPs), named feMPI, has been developed. FeMPI used TfR1 as a typical biomarker. The feMPI probe (SCIO-ICG-CRT-CPPs NPs, CCI NPs) consists of SCIO NPs, TfR1-targeting peptides (CRT), cell-penetrating peptides (CPPs), and indocyanine green (ICG). The specificity and sensitivity of CCI NPs in the MI/R mouse model were evaluated by MPI, magnetic resonance imaging (MRI), and near-infrared (NIR) fluorescent imaging. Results: The intensity of the MPI signal correlates linearly with the percentage of infarct area in MI/R stained by TTC, enabling a quantitative assessment of the extent of cardiac lesions. Notably, these findings are consistent with the standard clinical biochemical indicators in MI/R within the first 24 h. FeMPI detects cardiac injury approximately 48 h prior to the current clinical imaging detection methods of MI/R. Conclusion: The feMPI strategy can be a powerful tool for studying the process of MI/R-induced ferroptosis in vivo , providing clues for molecular imaging and drug development of ferroptosis-related treatments.
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Materials Today Bio
·
2024
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IF 8.7
Min Wang,Aoling Yu,Wen Han,Jingyi Chen,Chunhua Lu,Xiankun Tu
Ferroptosis, a newly discovered form of regulated cell death, has garnered significant attention in the field of tumor therapy. However, the presence of overexpressed glutathione (GSH) and insufficient levels of H 2 O 2 in the tumor microenvironment (TME) hinders the occurrence of ferroptosis. In response to these challenges, here we have constructed the self-assembled nanocomplexes (FeE NPs) utilizing epigallocatechin-3-gallate (EGCG) from green tea polyphenols and metal ions (Fe 3+ ) as components. After grafting PEG, the nanocomplexes (FeE@PEG NPs) exhibit good biocompatibility and synergistically enhanced tumor-inhibitory properties. FeE@PEG NPs can be disassembled by H 2 O 2 in the TME, leading to the rapid release of Fe 3+ and EGCG. The released Fe 3+ produces large amounts of toxic •OH by the Fenton reactions while having minimal impact on normal cells. The generated •OH effectively induces lipid peroxidation, which leads to ferroptosis in tumor cells. Meanwhile, the released EGCG can autoxidize to produce H 2 O 2 , which further promotes the production of •OH radicals and increases lipid peroxide levels. Moreover, EGCG also depletes the high levels of intracellular GSH, leading to an intracellular redox imbalance and triggering ferroptosis. This study provides new insights into advancing anticancer ferroptosis through rational material design, offering promising avenues for future research.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Xin Zheng,Xinyi Tang,Yinan Xu,Haiyan Zhu,Lianwei Zhong,Chen Chen,Jiajun Cui,Jie Zhou
Ethnopharmacological relevance The seed of Aesculus wilsonii Rehd., also known as Suoluozi in China, is a traditional Chinese herb included in the Pharmacopoeia of China (2020). Sodium aescinate (SA) is derived from the Aesculus wilsonii Rehd.’s seeds and is extensively used in clinical practice. Aim of the study The study investigated the involvement of the Nrf2/CTH pathway in SA-induced hepatotoxicity and explored potential strategies for alleviating SA-induced liver damage. Materials and methods The ICR mice and AML12 mouse hepatocytes were exposed to SA. The levels of Fe 2+ , cysteine (Cys), glutathione (GSH), hydrogen sulfide (H 2 S), ROS, lipid peroxides and caspase-3 activity were assessed. The effects of SA on signaling pathways related to ferroptosis and apoptosis were examined. Furthermore, genetic modification or agonists of Nrf2 and CTH were co-treated with SA. Results SA triggered ferroptosis and apoptosis in AML12 cells and mouse livers, characterized by a decline in Cys, GSH, and H 2 S levels, as well as accumulation of Fe 2+ , ROS and lipid peroxides, mitochondrial dysfunction, and chromatin condensation. SA decreased Nrf2, CTH, and Bcl-2 levels, elevated Bax levels, and activated caspase-9/3. Overexpression of Nrf2 or CTH, or NAC supplementation alleviated SA-induced ferroptosis by upregulating Cys and GSH levels. Overexpression of Nrf2 or CTH, or NaHS supplementation increased H 2 S levels, which reduced the interaction between p616-Drp1 and VDAC1 by enhancing Drp1 S-sulfenylation, thereby alleviating SA-induced mitochondrial-dependent apoptosis. Furthermore, DMF or Met mitigated SA-induced hepatotoxicity by activating the Nrf2/CTH pathway. Conclusions SA triggers oxidative stress, mitochondrial dysfunction, apoptosis, and ferroptosis, ultimately leading to liver damage by suppressing the Nrf2/CTH pathway.
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Communications Biology
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2025
·Vol. 8
·期 1
·1-16
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IF 5.1
Bie Pengfei,Su Dongpo,Gao Yang,Wu Liang,Niu Zhanfeng,Zhao Yanbin,He He,Jiang Zhanfeng,Zeng Zhong,Zhang Yaolin,Fan Heng,Xia Hechun
Microglia play significant roles in spinal cord injury (SCI) progression. Previous studies have suggested that ferroptosis plays a crucial role in exacerbating neuronal death following SCI; however, the role of microglial ferroptosis in SCI and the underlying mechanisms remain elusive. Here, we elucidate that lipid droplets accumulate in microglia to facilitate microglial ferroptosis after SCI. Notably, microglial ferroptosis peaks at 3 days post-injury, after which it decreases. Microglial Period 2 (Per2) expression is elevated after SCI in vivo; this change is highly synchronized with the changes in microglial ferroptosis. Microglia-specific Per2 knockout promoted neurological function recovery by suppressing microglial ferroptosis. In vitro, Per2 overexpression and deficiency amplified and mitigated microglial ferroptosis, respectively. RNA-seq indicated that Gpx4 was downregulated by Per2. Coimmunoprecipitation demonstrated that Per2 directly interacted with PPARα. Overall, our results indicate that Per2 determines the susceptibility of microglial ferroptosis via the PPARα-Gpx4 axis after SCI.
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Materials Today Bio
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2025
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IF 10.2
Peng Dong,Yun-Bo Chi,Deng-Ke Teng,Yuan-Qiang Lin,Ling-Yu Zhu,He-Qun Li,Jia-Yu Yang,Jia-Rui Du,Zong-Tao Zhang,Hai-Tao Ran,Guo-Qing Sui,Hui Wang,Qi-Meihui Wang
Ferroptosis, an iron-dependent, nonapoptotic form of regulated cell death, has become a new approach for antitumor treatment. However, the insufficient accumulation and poor penetration of ferroptosis inducers deep in tumors greatly limit their therapeutic effects. In this study, we constructed a cascade penetrating metal‒polyphenol ultrasonic molecular probe, Fe 3+ Cur-PFP@IR780-LIP (FCIPL). The nanoparticles (NPs) can penetrate deep into tumors in a stepwise fashion via specific targeting combined with cavitation effects resulting from acoustic droplet vaporization (ADV) and ultrasound-targeted microbubble destruction (UTMD) technology. Then, the drug can be successfully delivered into the mitochondria of tumor cells under the cascade response of ultrasound and the tumor microenvironment, inducing the ferroptosis domino cascade. The nanoparticles disassemble, releasing the Fenton reaction catalyst Fe 2+ and the ferroptosis inducer Cur, which together constitute the ferroptosis "amplifier," promoting the domino-like burst of lipid peroxide (LPO) and triggering ferroptosis. Simultaneously, the sonosensitizer IR780 is activated to induce sonodynamic therapy (SDT). Under the synergistic action of ferroptosis and SDT, a waterfall-like therapeutic effect is produced. In terms of diagnosis, this nanoplatform combines multimodal (ultrasound, photoacoustic, magnetic resonance and fluorescence) imaging to improve the diagnostic performance of anaplastic thyroid cancer (ATC) and provide a visualization strategy for early diagnosis. In this study, the advantages of ultrasound technology are exploited to achieve deep penetration of drugs and overcome the limitations of a single treatment modality, achieve optimal diagnostic and treatment effects, and provide new ideas for integrating ATC diagnosis and treatment.
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BIOMACROMOLECULES
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2025
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IF 5.4
Jing Qian,Duoduo Jiang,Zepeng Cui,Dmitri V. Krysko,Jia Tian,Weian Zhang
Photothermal therapy (PTT) is impeded by limited light penetration depth and cellular heat resistance induced by overexpressed heat shock proteins. Herein, we propose a ferrocene (Fc)-based supramolecular photothermal agent (PTA) to improve the therapeutic efficacy. Cy-Fc/CD-PEG not only had excellent photothermal effect but also possessed the ability to induce ferroptosis and immunotherapy. Cy-Fc/CD-PEG released Fc under intracellular acidic conditions. Then the Fe2+ of Fc could react with endogenous hydrogen peroxide (H2O2) to generate hydroxyl radicals (•OH) and Fe3+. The generated Fe3+ could be reduced to Fe2+ by depletion of intracellular glutathione (GSH), which promoted reactive oxygen species (ROS) generation via triggering the Fenton reaction and consuming GSH, leading to ferroptosis. Meanwhile, apoptotic tumor cells released abundant tumor-associated antigens, activating antitumor immunity. Both in vitro and in vivo experiments demonstrated excellent antitumor effects by the ferrocene-based Cy-Fc/CD-PEG supramolecular PTA. This work provided a PTT–ferroptosis combination strategy that activated antitumor immunity and inhibited tumor growth.
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Nature Communications
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2025
·Vol. 16
·期 1
·1-20
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IF 15.7
Bi Guoshu,Liang Jiaqi,Bian Yunyi,Shan Guangyao,Ren Shencheng,Shi Haochun,Huang Xiaolong,Zhu Junkan,Wang Qun,Jiang Wei,Gan Boyi,Zhan Cheng
Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN’s oxidoreductase function by occluding its active site. We also show that either restoring ALDH16A1 levels or inhibiting TXN significantly enhances the effectiveness of chemo/immunotherapy in a ferroptosis-dependent manner in SMARCA4-deficient NSCLC. Collectively, our findings elucidate an intricate SMARCA4-ALDH16A1-TXN stability/function dual regulatory axis that governs ferroptosis and informs a therapeutic strategy for overcoming resistance to chemotherapy or immunotherapy in SMARCA4-deficient NSCLC.
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Cell Metabolism
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2024
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IF 27.7
Hui Lin,Chuanshun Ma,Xiao Zhuang,Shuo Liu,Dong Liu,Mingxiang Zhang,Yan Lu,Guangjian Zhou,Chao Zhang,Tengwei Wang,Zihao Zhang,Lin Lv,Daolai Zhang,Xiong-Zhong Ruan,Yunfei Xu,Renjie Chai,Xiao Yu,Jin-Peng Sun,Bo Chu
G protein-coupled receptors (GPCRs) mediate most cellular responses to hormones, neurotransmitters, and environmental stimulants. However, whether GPCRs participate in tissue homeostasis through ferroptosis remains unclear. Here we identify that GPR56/ADGRG1 renders cells resistant to ferroptosis and deficiency of GPR56 exacerbates ferroptosis-mediated liver injury induced by doxorubicin (DOX) or ischemia-reperfusion (IR). Mechanistically, GPR56 decreases the abundance of phospholipids containing free polyunsaturated fatty acids (PUFAs) by promoting endocytosis-lysosomal degradation of CD36. By screening a panel of steroid hormones, we identified that 17α-hydroxypregnenolone (17-OH PREG) acts as an agonist of GPR56 to antagonize ferroptosis and efficiently attenuates liver injury before or after insult. Moreover, disease-associated GPR56 mutants were unresponsive to 17-OH PREG activation and insufficient to defend against ferroptosis. Together, our findings uncover that 17-OH PREG-GPR56 axis-mediated signal transduction works as a new anti-ferroptotic pathway to maintain liver homeostasis, providing novel insights into the potential therapy for liver injury.
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Antioxidants
·
2025
·Vol. 14
·期 8
·914
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IF 6.6
Pengxin Jiang,Kangping Liu,Yanan Cui,Puyu Liu,Xutao Wang,Zijuan Hou,Jiamei Cui,Ning Chen,Jinghui Fan,Jianguo Li,Yuzhu Zuo,Yan Li
EnterotoxigenicEscherichia coli(ETEC) leads to severe diarrhea in piglets. Naringenin (Nar), a natural flavonoid compound, is known for its antibacterial and anti-antioxidant properties. However, the protective effects of Nar against ETEC-induced diarrhea have not been reported yet. This study investigated the protective mechanisms of Nar against ETEC infection in porcine intestinal epithelial cells (IPEC-J2). ETEC infection induced oxidative stress and ferroptosis in IPEC-J2 cells by elevating intracellular iron content and ROS accumulation, increasing MDA levels, downregulating SOD activity and GPX4 expression, and upregulating the transcription of CHAC1 and SLC7A11. In contrast, Nar suppressed ETEC-induced ferroptosis of IPEC-J2 cells by inhibiting the SLC7A11/GPX4 pathway. Specifically, Nar mitigated mitochondrial damage, reduced intracellular iron levels and ROS accumulation, and ultimately reversed the oxidative stress. Network pharmacology and molecular docking identified heat-shock protein 90 (HSP90) as a potential target of Nar. Overexpression and knockdown experiments revealed that ETEC-induced ferroptosis was mediated by upregulation of HSP90, while the protective effects of Nar against ETEC-induced ferroptosis were dependent on the downregulation of HSP90. In conclusion, Nar targets host HSP90 to protect IPEC-J2 cells from ferroptosis caused by ETEC infection. This study demonstrates that Nar is a potent antioxidant natural compound with potential for preventing ETEC-induced intestinal damage.
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