NEUROCHEMICAL RESEARCH
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2025
·Vol. 50
·期 1
·1-17
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IF 3.8
Min Xiao-li,Shi Ying,Xu Ying,Li Yu-ye,Dong You-kang,Chen Fei-xiong,Chen Quan-ming,Sun Yu-long,Liao Rui,Wang Jia-ping
Objective: Post-resuscitation brain injury is a common sequela after cardiac arrest (CA). Increasing sirtuin1 (SIRT1) has been involved in neuroprotection in oxygen-glucose deprivation (OGD) neurons, and we investigated its mechanism in post-cardiopulmonary resuscitation (CPR) rat brain injury by mediating p65 deacetylation modification to mediate hippocampal neuronal ferroptosis. Methods: Sprague-Dawley rat CA/CPR model was established and treated with Ad-SIRT1 and Ad-GFP adenovirus vectors, or Erastin. Rat postoperative neurological function, and cognitive and learning abilities were assessed by neurological deficit score and Morris water maze test. Hippocampal neuronal pathological changes and injury were evaluated by H&E and TUNEL staining. Serum brain injury biomarkers and hippocampal inflammatory factors and SIRT1 mRNA levels were determined by ELISA and RT-qPCR. OGD/reoxygenation (OGD/R) rat hippocampal neuron (H19-7) model was established. Cell viability and injury, nuclear factor-kappa B (NF-κB) p65 localization, iron content, and levels of glutathione, malondialdehyde, reactive oxygen species, SIRT1, Ac NF-κB p65 (Lys310), NF-κB p65, ACSL4, glutathione peroxidase 4 and SLC7A11 were measured. Results: In CA/CPR rats, SIRT1 was down-regulated, and SIRT1 overexpression alleviated cerebral injury. SIRT1 overexpression inhibited OGD/R-induced H19-7 cell ferroptosis to ameliorate cell injury, and inactivated the NF-κB pathway by reducing p65 acetylation to hinder its entry into the nucleus. Inactivating the NF-κB pathway reduced OGD/R-induced ferroptosis and alleviated cell injury. SIRT1 alleviated cerebral injury by mediating p65 deacetylation to inhibit hippocampal neuronal ferroptosis mediated by the NF-κB pathway. Conclusions: SIRT1 inhibited the NF-κB signaling pathway-mediated hippocampal neuronal ferroptosis by mediating p65 deacetylation modification, thereby alleviating brain injury in CA/CPR rats.
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FOOD AND CHEMICAL TOXICOLOGY
·
2025
·
IF 3.5
Ziyang Huang,Ruijia Xu,Zhongjun Wan,Chao Liu,Jinquan Li,Jun He,Li Li
Cadmium (Cd) is a prevalent heavy metal pollutant known to cause lung damage. However, the mechanisms underlying Cd-induced lung injury and the associated therapeutic strategies remain unclear. By establishing Cd-induced lung damage models both in vivo and in vitro , we observed that Cd inhibited the Nrf2/HO-1 signaling pathway, disrupted the redox balance in lung tissue, accelerated endoplasmic reticulum (ER) stress, and promoted ferroptosis, ultimately leading to lung injury. Melatonin (Mel), a potent reactive oxygen species (ROS) inhibitor with high antioxidative efficacy, mitigated the increasing in ROS and the decreasing in superoxide dismutase levels induced by Cd, as well as the upregulation of PERK-eIF2α-ATF4 signaling associated with ER stress, through the activation of the Nrf2/HO-1 signaling pathway. Furthermore, Mel administration not only prevented Cd-induced iron overload but also reduced lipid peroxidation levels, thereby improving mitochondrial morphological alterations. Collectively, our results demonstrated that Mel treatment alleviated Cd-induced lung injury by inhibiting oxidative stress, which in turn ameliorated ER stress and ferroptosis through the activation of the Nrf2/HO-1 pathway.
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Advanced Healthcare Materials
·
2024
·
IF 10
Yueqi Ni,Yuanyuan Hu,Lijia Zhu,Xulin Jiang,Hong Zhang,Jia Liu,Yin Zhao
Retinal ischemia‒reperfusion (IR) is a major contributor to vision impairment and irreversible vision loss due to retinal ganglion cell (RGC) injury or loss. Contemporary therapeutic approaches predominantly focus on the amelioration of symptoms rather than addressing the fundamental etiological factors. Oxidative stress is a notable feature and an important mediator of IR damage. Lycium barbarum polysaccharide (LBP), the main active ingredient of Lycium barbarum, has various pharmacological effects, including antioxidation, immunoregulation, and neuroprotective effects. In this study, the ROS-consumable moiety phenylboronic acid pinacol ester (PBA) is introduced to LBP molecules, which can self-assemble into nanoparticles in aqueous solution. This nanoparticle (termed PLBP) can reduce the cellular ROS levels and enhance the antioxidant capability of RGCs by activating the NRF2 pathway, thus protecting RGCs from ferroptosis and preserving visual function in response to IR injury. PLBP also reduces neuroinflammation by inhibiting the ability of microglia to phagocytose, migrate, secrete inflammatory cytokines, and activate the NF-κB pathway. In conclusion, this approach can be used as an inspiration for the future development of neuroprotective drugs.
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JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Ping Wu,Juan Zhao,Haowen Qiao,Kaihang Yu,Yanfang Zhao,Xiaolei Meng,Luyang Ye,Yunhao Cai,Xinwang Ying,Liuxi Chu,Junpeng Xu,Junqing Huang,Dawei Jiang,Qian Xu,Shengcun Li,Lizhu Yang,Lihua Luo,Sipin Zhu,Zhiqiang Luo,Qi Dong,Yingshan Zhou,Xiaokun Li,Zhouguang Wang
Ferroptosis-induced oxidative stress triggers mitochondrial damage in spinal cord injury (SCI), impairing residual neuronal function and driving microglial M1 polarization. Regulating neuronal mitochondrial function is an urgent problem in the field of tissue engineering. To address this, an injectable dual-network hyaluronic acid/black phosphorus (BP)/ fibroblast growth factor 21 (FGF21) composite hydrogel (ADBF) is explored, and the successful application of this functional hydrogel in SCI repair is demonstrated. The two-dimensional BP matrix enables high-efficiency loading of macromolecular drugs such as FGF21. Sustained FGF21 release from ADBF reduces neuronal oxidative stress and mitigates neurodegeneration. Subsequent exposure of BP nanosheet surfaces enhances cation adsorption (e.g., iron ions), thereby inhibiting ferroptosis. In a mouse model of SCI, behavioral, electrophysiology and immunohistochemistry investigations suggested that the composite ADBF hydrogels can effectively promote functional repair by enhancing remyelination, accelerating axonal regeneration, inhibiting neurons ferroptosis and regulating immune microenvironment of nerve regeneration. Mechanistically, ADBF attenuates ferroptosis by restoring mitochondrial function via the AMPK/AKT signaling axis, consequently promoting microglial M2 polarization. This strategy of integrating BP/FGF21 nanosheets into an injectable conductive hydrogel provides new insight into designing advanced anti-ferroptosis therapy biomaterials for SCI repair.
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ADVANCED MATERIALS
·
2025
·
IF 26.8
Bin Liu,Xiaorui Chen,Yanlin Zhu,Hao Chen,Jia Tan,Zhuang Yang,Jing Li,Pan Zheng,Lili Feng,Qingqing Wang,Shili Gai,Lei Zhong,Piaoping Yang,Ziyong Cheng,Jun Lin
To improve the efficiency and application prospects of metal peroxides in tumor therapy, the synthesis of bimetallic peroxides via simple yet effective approaches will be highly significant. In this work, hyaluronic acid modified zinc-copper bimetallic peroxides (ZCPO@HA) nanoparticles are synthesized through a one-step symbiotic method by co-hydrolysis of zinc acetate and copper acetate in weakly alkaline solution, followed by modification with sodium hyaluronate. Upon decomposition in the tumor microenvironment, ZCPO@HA nanoparticles can generate a considerable content of hydroxyl radical (·OH) by Fenton-like reaction between Cu 2+ and self-compensating hydrogen peroxide, while downregulating the expression of glutathione peroxidase 4 to induce ferroptosis. The abundant release of Cu 2+ leads to the aggregation of dihydrolipoamide S-acetyltransferase and the reduction of iron-sulfur cluster proteins, causing cuproptosis. The immunogenic cell death of tumor cells releases abundant damage associated molecular patterns, effectively activating the adaptive immune response. Zn 2+ and ·OH cause mitochondrial damage, leading to the release of a substantial amount of mitochondrial DNA. This subsequently activates the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway, enhancing the innate immune response. In conclusion, it synthesizes a new type of bimetallic peroxides by one-step symbiosis for activating anti-tumor immunotherapy combined with immune checkpoint inhibitor.
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Biomaterials Advances
·
2022
·
IF 0
Sen Lin,Wa Gao,Chenchen Zhu,Qi Lou,Cong Ye,Yueping Ren,Rashid Mehmood,Baoshan Huang,Kaihui Nan
Traumatic optic neuropathy (TON) is the major contributor to optic nerve damage, where the retinal ganglion cells (RGCs) are substantially lost. However, the underlying pathological mechanisms for these conditions remain largely elusive. Present work conducted a study on TON rat model, where the iron-dependent cyclooxygenase-2 (COX-2) overexpression and lipid peroxidation were observed in RGCs, suggesting ferroptosis, an iron-dependent non-apoptotic cell death, is involved in TON-induced death of RGCs. Hence, the newly formulated hyaluronic acid (HA)-based deferoxamine (DFO) nanoparticles (DFO-NPs) were intravitreally administrated in the rat model. It was hypothesized that the effective delivery of DFO, iron chelator, to the RGCs might rescue RGC ferroptosis from TON-induced injury. Also, since DFO is poor in bioavailability and of very short half-life in vivo , its safe and efficient intravitreal delivery is critical. Therefore, DFO-NPs were prepared by chemical grafting DFO onto HA molecules, and then crosslinking them in microemulsion bubbles for nanoparticles formulation. The nanoparticles were highly accumulated around the ganglionic cells and DFO uptake was increased in RGCs, accompanied by the significantly inhibited the overexpression of COX-2 and inactivation of glutathione peroxidase 4 (GPX4). These results indicate that DFO-NPs acted as an effective ferroptosis inhibitor, for the prevention of TON-induced RGC death. The current study provides new insights into the underlying mechanism of TON-induced RGC death, which may help to explore a novel strategy for the treatment of TON.
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JOURNAL OF NEUROTRAUMA
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2023
·
IF 4.2
Hongxing Tang,Kejun He,Kun Zhao,Chen Zheng,Weichi Wu,Weilin Jin,Lixuan Yang,Baoshu Xie
Hinokitiol (β-thujaplicin, HIK) is a natural monoterpene small molecule compound showing various biological effects including antibacterial, anti- inflammatory and anti-tumor. Ferroptosis, a new form of iron-dependent cell death, has been demonstrated as one of the pathophysiological mechanisms of traumatic brain injury (TBI). However, the effect of hinokitiol on neuronal ferroptosis after traumatic brain injury has not been reported. Here, we show that hinokitiol alleviated excessive glutamate-induced intracellular reactive oxygen species (ROS), lipid peroxidation, and Fe2+ accumulation in HT-22. Moreover, hinokitiol upregulated heme oxygenase-1 (HO-1) expression, promoted nuclear factor-erythroid factor 2-related factor 2 (Nrf2) nuclear translocation, and inhibited the activation of microglia and astrocyte after TBI. Furthermore, hinokitiol remarkably reduced brain tissue lesions, mitigated neuron loss, iron deposition and attenuated neurologic impairment in the CCI-constructed TBI model in vivo. These results suggest that hinokitiol has neuroprotective effects on rescuing cells from TBI-induced neuronal ferroptosis. In summary, we reveal a novel role of hinokitiol in TBI, which has neuroprotective effects on rescuing cells from TBI-induced neuronal ferroptosis. Moreover, hinokitiol through activating the Nrf2/Keap1/HO-1 signaling pathway significantly reduces the neuronal damage, suggesting that it is a potential therapeutic candidate for TBI.
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Stress Biology
·
2025
·Vol. 5
·期 1
·74
·
IF 5.8
Li Jie,Jiang Enhui,Zhang Mengyang,Pan Chuanying,Lei Chuzhao,Han Lin,Lan Xianyong
Ferroptosis has been increasingly implicated in adipose and muscle dysfunction, systemic metabolic disturbances, and several diseases in livestock, which necessitates effective and side-effect-free inhibition strategies. Phloretin, a dihydrochalcone with excellent antioxidant and anti-inflammatory properties, may have the potential to restrain cell ferroptosis. Herein, phloretin was verified to significantly inhibit (1S,3R)-RSL3-induced ferroptosis by reducing intracellular MDA, Fe 2 ⁺, and ROS levels and restoring cell total antioxidant capacity in bovine and mouse preadipocytes or myoblasts. It also alleviated oxidative stress (OS), a vital inducer of ferroptosis, by restoring antioxidant enzyme activity in the above cells and obese mice. In vivo, phloretin gavage significantly reversed the trend where high-fat diet (HFD)-induced OS promoted the expression of ferroptosis-promoting genes and proteins (e.g., ACSL4 and PTGS2) while inhibiting the expression of ferroptosis-negative regulators (e.g., Fth1 and Gpx4 ). Unlike most flavonoids that exert anti-inflammatory or antioxidant activities by altering the gut microbiota composition, metagenomic sequencing analysis of cecal contents from phloretin-gavaged and HFD mice revealed that phloretin exerts its antioxidative and ferroptosis-inhibitory effects independent of modulating gut microbiota diversity. Further transcriptomic analyses of mouse adipose tissues revealed that phloretin alleviated ferroptosis in adipocytes by modulating the transcription of genes enriched in AMPK and PPAR signaling pathways, such as Camkk2 . Hence, based on multi-omics analysis combined with in vivo and in vitro verification, phloretin effectively alleviated the OS to further inhibit ferroptosis of adipose or muscle cells through the AMPK-PPAR pathway, which can provide new research ideas for ameliorating adipose or myocyte dysfunction induced by ferroptosis in animals. Graphical
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ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2025
·Vol. 57
·期 10
·1647
·
IF 3.4
Guandi Ma,Min Lei,Shuang Guo,Yuqing Zhang,Yixuan Sun,Huimin Ji,Changhan Ouyang,Xiaosong Yang,Youzhi Zhang,Xiufen Liu,Baoqing Zhao,Xiying Guo
Schisandrin A (SchA), a bioactive lignan that was isolated from the dried fruit of Schisandra chinensis , has attracted much attention because of its diverse spectrum of pharmacological effects. The aim of this study is to clarify the function of SchA in diabetes-related fear memory impairment and its molecular mechanisms. Rats are randomly assigned to 4 groups: the control group (Con group), the DM group, the DM + SchA group, and the Con + SchA group. The results demonstrate that SchA treatment improves insulin sensitivity, reduces blood glucose, and significantly reduces memory impairment. SchA treatment also prevents histological damage, enhances synaptic protein production, and significantly decreases Aβ 42 formation in the diabetic prefrontal cortex. Further research reveals that SchA therapy decreases microglial activation and the expression levels of variables linked to inflammation while increasing the phosphorylation of proteins implicated in the insulin resistance signaling pathway. Furthermore, in the prefrontal cortex of diabetic rats, SchA decreases ferroptosis by increasing the protein expressions of GPX4, SLC7A11, Nrf2, HO-1, and SIRT1. Overall, our findings suggest that SchA may lessen diabetes-associated fear memory impairment symptoms by, most likely, lowering ferroptosis and inflammatory responses in the prefrontal brain of diabetic rats. SchA may be a useful therapy for diabetes, including memory impairment.
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ACS Applied Bio Materials
·
2025
·
IF 4.7
Xueqi Liang,Yingying Cai,Zhen Liu,Nan Wang,Ahmed Mohamed Omer,Junhong Ling,Xiao−kun Ouyang
Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation and redox imbalance, has emerged as a promising strategy for treating drug-resistant cancers. However, its therapeutic efficacy is often limited by the antioxidant-rich tumor microenvironment (TME), which inhibits reactive oxygen species (ROS) accumulation. In this study, we introduced a tumor-responsive nanoplatform (MLCT) designed to synergistically amplify ferroptosis through a combination of iron catalysis, calcium overload, nitric oxide (NO) release, and photothermal stimulation. The MLCT platform consisted of mesoporous polydopamine (MPDA), calcium peroxide (CaO2), l-arginine (LA), and a tannic acid-Fe3+ (TA-Fe) shell, facilitating TME-responsive release of therapeutic agents. In vitro, MLCT effectively depleted glutathione (GSH) and sustained NO generation, resulting in elevated ROS levels and mitochondrial dysfunction. Additionally, upon near-infrared (NIR) irradiation, localized hyperthermia further potentiated ferroptotic activity. In vivo, MLCT combined with NIR treatment resulted in an 86.34% reduction in tumor growth, with minimal systemic toxicity. These results highlighted the potential of MLCT as a precision-engineered ferroptosis platform for enhanced cancer therapy.
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PHARMACEUTICAL BIOLOGY
·
2025
·
IF 4.8
Yong-xiang Huang,Jin-ru Zhang,Shi-hua Fu,Zhe Liu,Hui-jun Zhong,Qing-yang Zhong,Yin-di Luo,Ying-jie Hu,Hai-peng Zhu,Bin Wen,Song Chen
Context Macrophages play a critical role in the pathogenesis of ulcerative colitis (UC). Indirubin (IDR), a natural ligand of the aryl hydrocarbon receptor (AhR), has been shown to ameliorate DSS-induced colitis in our previous study (Liu Z et al.).Objective To investigate whether IDR exerts its protective effects by regulating M1/M2 polarization and inhibiting ferroptosis in macrophages.Materials and Methods Immunohistochemistry staining targeting CD206 and F4/80 was performed to evaluate the effect of IDR on the polarization of M1/M2 macrophages in colitis. Subsequently, the effects of IDR on the M1- or M2-polarization of THP-1-derived macrophages were investigated. Furthermore, the effects of IDR on ferroptosis in the colon tissue of mice and on RSL3-induced ferroptosis in THP-1-derived macrophages were assessed. The results were verified in mouse peritoneal macrophages.Results In addition to reducing the infiltrated macrophages, IDR treatment preserved CD206+ macrophages in DSS-induced colitis. Using cultured THP-1 cells, we demonstrated that IDR inhibited M1 polarization and prompted M2 polarization. Furthermore, we showed that IDR treatment decreased levels of 4-HNE while increasing GPX4 and NRF2 in DSS-induced colitis and THP-1 cells. IDR treatments also reduced cellular reactive oxygen species (ROS) and iron content, and mitigated RSL3-induced ferroptosis in THP-1-derived macrophages. Similarly, IDR augmented M2-polarization and alleviated ferroptosis in peritoneal macrophages.Discussion and Conclusion IDR skews the polarization of macrophages from M1 to M2. Furthermore, it inhibits ferroptosis in both mice and THP-1-derived macrophages. These mechanisms may contribute to the therapeutic effects of IDR in the treatment of UC.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2025
·
IF 8.2
Yan Zhang,Yuanyuan Ren,Zhen Wang,Xi Zhang,Xiaofang Li,Yi Yu,Lu Qian,Yuyan Xiong
A high-fat diet and obesity significantly increase the risk of gastric cancer (GC), with persistent obesity contributing to a notable rise in GC incidence. However, the underlying molecular mechanisms remain largely unclear. In this study, we identified exosomal SLC1A5 (Exo-SLC1A5) as a novel senescence-associated secretory phenotype (SASP) factor that promotes GC malignancy. Exosomal SLC1A5 drives GC progression by suppressing ferroptosis in a GPX4-dependent manner. Mechanistically, in the context of obesity, senescent endothelial cells release exosomal SLC1A5, which engages EGFR on GC cells, triggering SRC phosphorylation at Tyr416 and subsequent YAP1 activation at Tyr357. This leads to YAP1 interaction with MYO1B to enhance the nuclear translocation of YAP1, and subsequent upregulation of GPX4, resulting in ferroptosis suppression and accelerated GC progression. In vivo, depletion of exosomal SLC1A5 from PA-induced senescent ECs attenuated GC tumor growth and metastasis in a xenograft mouse model. These findings reveal a novel mechanism by which exosomal SLC1A5 promotes GC progression through the EGFR/SRC/YAP1/GPX4 signaling axis. Targeting the Exo-SLC1A5/EGFR/SRC/YAP1/GPX4 axis may provide a therapeutic strategy for GC.
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