BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Mingyue Tan,Yunfei Yin,Weixiang Chen,Jun Zhang,Yifeng Jin,Yue Zhang,Lei Zhang,Tingbo Jiang,Bin Jiang,Hongxia Li
Ferroptosis is a newly defined mode of cellular demise. The increasing investigation supports that ferroptosis is a crucial factor in the complex mechanisms of myocardial ischemia–reperfusion (I/R) injury. Hence, targeting ferroptosis is a novel strategy for treating myocardial injury. Although evidence suggests that trimetazidine (TMZ) is potentially efficacious against myocardial injury, the exact mechanism of this efficacy is yet to be fully elucidated. This study aimed to determine whether TMZ can act as a ferroptosis resistor and affect I/R-mediated myocardial injury. To this end, researchers have constructed in vitro and in vivo models of I/R using H9C2 cardiomyocytes, primary cardiomyocytes, and SD rats. Here, I/R mediated the onset of ferroptosis in vitro and in vivo, as reflected by excessive iron aggregation, GSH depletion, and the increase in lipid peroxidation. TMZ largely reversed this alteration and attenuated cardiomyocyte injury. Mechanistically, we found that TMZ upregulated the expression of Sirt3. Therefore, we used si-Sirt3 and 3-TYP to interfere with Sirt3 action in vitro and in vivo, respectively. Both si-Sirt3 and 3-TYP partly mitigated the inhibitory effect of TMZ on I/R-mediated ferroptosis and upregulated the expression of Nrf2 and its downstream target, GPX4-SLC7A11. These results indicate that TMZ attenuates I/R-mediated ferroptosis by activating the Sirt3-Nrf2/GPX4/SLC7A11 signaling pathway. Our study offers insights into the mechanism underlying the cardioprotective benefits of TMZ and establishes a groundwork for expanding its potential applications.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2025
·Vol. 54
·期 6
·1-14
·
IF 3.9
Wei-Wei Zheng,Jia-Xuan Ding,Yang-Xin Liang,Ling Ye
Thymoquinone (TQ) is a quinone isolated from the black seed Nigella sativa and has been extensively investigated in the pharmaceutical field due to its promising therapeutic value. There have been reports on the potential anti‑cancer properties of TQ, whereas the clinical application of TQ is greatly restricted by its low water solubility and poor delivery. In the present study, TQ was encapsulated into hydroxypropyl‑β‑cyclodextrin (HP‑β‑CD) using the freeze‑drying method to form a TQ/HP‑β‑CD inclusion complex. Then, the TQ/HP‑β‑CD inclusion complex was characterized by Fourier transform infrared, differential scanning calorimetry, X‑ray diffraction and scanning electron microscopy. HP‑β‑CD as an excipient significantly enhances the water solubility of TQ, and TQ/HP‑β‑CD demonstrated excellent biocompatibility on normal cells both in vitro and in vivo. Moreover, the complexation with HP‑β‑CD enhanced the anticancer activity of TQ against non‑small cell lung cancer cells and its mechanism of action is related to ferroptosis mediated by NF‑κB. Such an enhanced cytotoxic effect may be attributed to the effective complexation of TQ in HP‑β‑CD, which enhances its water solubility and bioavailability.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 7
·e70174
·
IF 4.2
Zhenfei Yu,Xiaoling Qian,Weihua Wu,Meiqi Zhang,Ying Li
Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains unclear. In this study, we investigated the protective effects and mechanisms of baicalin in ICH using an ICH mouse model. ICH mouse model was established by injection of collagenase type IV into intracranial in C57BL/6 mice. Neurological function was evaluated by neurological severity scores and the rotarod test. Hemorrhagic foci of brain was evaluated by TTC and hematoxylin−eosin staining. Iron ion deposition in brain was detected by Prussian blue staining. Ferroptosis was evaluated by measuring expression of FTH-1, SLC7A11, GPX4, and TFRC, as well as detecting iron content and levels of glutathione (GSH) and malondialdehyde (MDA). GPX4 expression and apoptosis of brain were detected by immunofluorescence staining and TUNEL assay. Results showed that baicalin improved neurological function and reduced the area of hemorrhagic foci of brain in ICH mouse model. Baicalin decreased iron ion deposition, inhibited ferroptosis and apoptosis, and upregulated GPX4 in brain of ICH mouse model. Moreover, baicalin increased AKT1 phosphorylation and the protein level of Nrf2 in brain of ICH mouse model. Notably, AKT1 inhibitor LY294002 and Nrf2 inhibitor reversed the effects of baicalin on the activation of AKT1/Nrf2/GPX4 axis and the inhibition of ferroptosis in brain of ICH mouse model. Collectively, we demonstrated that baicalin promotes ICH recovery by inhibiting ferroptosis in brain tissue through activation of AKT/Nrf2/GPX4 axis. These results may provide new insights for the study of baicalin in the treatment of ICH.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Xinwen Dong,Zheng Luo,Cuiying Li,Jie Gao,Yue Ma,Xiaoran Ma,Jiahang Yang,Sanqiao Yao,Weidong Wu,Yichun Bai,Qunwei Zhang,Wenjie Ren
Gas explosion (GE) exposure led to significant neuropathology in rats. • GE induced JNK/p38 MAPK pathway activation, ferroptosis, and inflammation. • Sodium butyrate mitigated these effects by inhibiting JNK/p38 MAPK activation. This study investigated the neuroprotective effects of sodium butyrate (NaB) against gas explosion (GE)-induced traumatic brain injury (TBI), with particular emphasis on its modulation of ferroptosis. GE exposure was simulated using a shock tube in vivo and a shockwave therapy instrument in vitro . A comprehensive assessment was performed, including behavioral tests, histopathological examination, molecular analyses (c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4), and interleukin-6 (IL-6)/interleukin-10 (IL-10)/tumor necrosis factor-α (TNF-α)), and in vitro validation using a CTX TNA2 rat astrocyte/H19-7 rat hippocampal neuron/GMI-R1 rat microglia (CTX/H19-7/GMI-R) tri-culture system. Pharmacological inhibition with SP600125 (a JNK inhibitor), SB203580 (a p38 MAPK inhibitor), and ferrostatin-1 (Fer-1, a ferroptosis inhibitor) was employed to confirm pathway involvement. GE exposure induced profound neuropathological changes, characterized by mitochondrial cristae disruption, inflammatory cell infiltration, and locomotor deficits. At the molecular level, GE exposure activated the JNK/p38 MAPK pathway (as evidenced by increased JNK and p38 phosphorylation), triggered ferroptosis (elevated Fe 2+ and malondialdehyde levels, with reduced GPX4 and SLC7A11 expression), and elicited a pro-inflammatory response (increased IL-6 and TNF-α, decreased IL-10). NaB administration effectively counteracted these deleterious effects by restoring redox homeostasis, suppressing JNK/p38 activation, and rebalancing inflammatory cytokine profiles. Notably, co-administration of pathway inhibitors potentiated the protective effects of NaB, further corroborating the involvement of JNK/p38 MAPK-mediated ferroptosis in GE-induced TBI. Collectively, these findings indicate that NaB attenuates GE-induced TBI and ferroptosis, likely through inhibition of the JNK/p38 MAPK signaling pathway. Download: Download high-res image (288KB) Download: Download full-size image
✓ 已验证
产品关联
DOI
高影响因子
Small
·
2026
·
IF 11.8
Chunrong Ren,Ruxi Deng,Jiameng Ding,Wuyang Wei,Hai Wang,Ying Liu,Li Ding,Meiqi Chang,Yu Chen,Yang Zhou
Hepatocellular carcinoma, a malignant tumor with high incidence and mortality rates, urgently requires the development of novel therapeutic strategies that are highly efficient and minimally toxic. Sonodynamic therapy has garnered significant attention due to its non-invasiveness, deep tissue penetration capability, and low side effects, yet its efficacy is highly dependent on the development of high-performance sonocatalyst. This study successfully prepared Pd-integrated indium oxide with abundant structural defects as a novel sonocatalyst for the highly efficient sonocatalytic eradication of hepatocellular carcinoma. Furthermore, Pd confers catalase-like and peroxidase-like enzymatic activities, modulating the tumor microenvironment to alleviate hypoxia and augment hydroxyl radical production, consequently amplifying sonocatalytic efficacy. Mechanistic insights identify a synergistic pathway involving both apoptosis and ferroptosis. This hybridized apoptotic/ferroptotic pathway acts synergistically to amplify oxidative cellular damage, ultimately achieving significant suppression and eradication of hepatocellular carcinoma. This work not only provides a novel strategy for designing efficient sonosensitizers through defect engineering but also unveils a new mechanism whereby engineered sonocatalysts can treat cancer by triggering hybridized cell death pathways, offering a promising approach and theoretical foundation for the sonodynamic therapy of liver cancer.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2026
·
IF 13.6
Xiaoxian Huang,Lu Wang,Qiutong Guan,Lin Chen,Hengkai Qi,Haiying Wang,Yue Qian,Dake Song,Qijun Hui,Hanrui Yu,Minjie Wei,Wensheng Zheng,Zhenhua Li
Ferroptosis represents a promising antitumor strategy, yet its efficacy in colon cancer is compromised by excessive antitioxidant glutathione (GSH) and insufficient reactive oxygen species (ROS). To address this limitation, we rationally designed integrated nanoplatforms (FeBMnDC NPs) by covalently conjugating albumin-MnO 2 complexes with ferritin to codeliver the ROS-responsive dihydroartemisinin (DHA) dimer and photosensitizer Chlorin e6 (Ce6). This design synergistically disrupts redox homeostasis to induce ferroptosis and immune activation. Upon tumor accumulation and laser irradiation, the FeBMnDC NPs release oxygen, Mn 2+ , ferritin, DHA, and Ce6. Laser-triggered ROS initiates a self-amplifying feedback loop that further releases DHA and Ce6, enhancing ROS generation via chemodynamic and photodynamic therapies, while MnO 2 degradation and ferric ion reduction deplete GSH. Severe oxidative stress promotes apoptosis, ferroptosis, and immunogenic cell death. In vitro and in vivo studies confirmed that FeBMnDC NPs enhance lipid peroxidation and dendritic cell maturation, achieving potent antitumor efficacy without apparent side effects. Moreover, integrated transcriptomic and proteomic analyses revealed that laser irradiation reprograms GSH metabolism and activates ferroptosis-executing pathways, identifying AMPD3 as a novel ferroptosis-associated gene in colon cancer. This work presents a self-amplifying nanoplatform enabling multimodal redox intervention, offering a mechanism-driven strategy for colon cancer treatment.
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Hai Huang,Liwei Guo,Hansong Sun,Yunhong Liu,Jun Zhang,Weijie Tang,Xiaodong Xia,Yu Wang,Ni Chen,Dong Lv,Jing Yang
Objective To investigate the mechanism of action of saikosaponin D (SSD) on bladder cancer (BCa) and evaluate its synergistic antitumor efficacy with the chemotherapeutic agent gemcitabine (GEM). Methods MTT, colony formation, Transwell, and scratch wound healing assays detected SSD's effects on the proliferation, invasion, and migration of RT112 and T24 cells. Specific inhibitors identified cell death mode. Western blotting, immunohistochemistry, and flow cytometry verified ferroptosis-related protein expression and oxidative stress. Network pharmacology predicted core pathways, validated by examining PI3K/AKT pathway activity. Animal models evaluated the synergistic effect of SSD and GEM. Results In vitro, SSD dose-dependently inhibited the BCa cells proliferation, invasion, and migration, and upregulating E-cadherin whilst downregulating N-cadherin, Vimentin, and Snail. The effects were blocked by the ferroptosis inhibitor Fer-1. Network pharmacology identified the PI3K/AKT pathway as a core target. Moreover, SSD regulated the GPX4/SLC7A11/ACSL4, suppressed PI3K/AKT phosphorylation, and triggered lipid peroxidation and reactive oxygen species accumulation, partially reversed by a PI3K-specific phosphopeptide agonist. In vivo, SSD inhibited tumor growth, and its combination with GEM showed superior efficacy. The combination therapy most effectively downregulated SLC7A11, GPX4, Vimentin, N-cadherin and Snail, while upregulating the ACSL4 and E-cadherin. Conclusion SSD inhibits the malignant phenotype of BCa by targeting PI3K/AKT to trigger ferroptosis. Its synergistic effect with GEM from the dual mechanisms of ferroptosis sensitization and epithelial-mesenchymal transition inhibition, providing an innovative combination strategy based on natural product active ingredients to overcome bladder cancer chemoresistance.
✓ 已验证
DOI
PubMed
高影响因子
Advanced Science
·
2026
·
IF 14.1
Tingting Zhang,Mengyi Xu,Yan Zhang,Zhiwen Li,Danqing Song,Jing Pang,Ke Li,Yanxiang Wang
Bacterial-based materials, leveraging their inherent hypoxia and immunosuppressive microenvironment-targeting capabilities, immunomodulatory effects, and drug delivery advantages, have emerged as promising strategies to modulate the tumor microenvironment (TME) for converting immunologically “cold” tumors into “hot” ones. This study innovatively functionalizes Lactobacillus reuteri ( L. reuteri ) using metal-phenolic networks (MPNs) to co-deliver αPD-L1 antibodies and gallium ions (Ga 3 + ) for synergistic anti-tumor therapy. The MPN coating materials enable pH-responsive drug release, whereby αPD-L1 reverses immunosuppression and Ga 3 + disrupts tumor iron metabolism, mimicking Fe 3 + to induce selective ferroptosis. In vivo evaluations in B16 and LLC tumor-bearing mouse models revealed that functionalized L. reuteri had the potential to reprogram the tumor immune microenvironment and significantly enhanced tumor regression. This system achieved multifunctional tumor regression in vivo, integrating bacterial hypoxia-driven chemotaxis, MPN-mediated ferroptosis, and immune checkpoint inhibitors (ICIs)-driven immune activation. Thus, the multifunctional materials offer a novel strategy for treating refractory or immunologically “cold” tumors.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Shenghui Zhang,Qin Liu,Bo Chen,Hui Chang,Ying Pan,Yanli Liu,Xin Zhao,Juntang Lin
MenSC-EVs alleviate STZ-induced ovarian dysfunction in diabetic mice. • MenSC-EVs suppress high-glucose-induced ferroptosis in granulosa cells. • EV-associated HSPA5 mediates protection via AKT/mTOR–BECN1/SLC7A11 signaling. Type 1 diabetes mellitus (T1DM) is associated with ovarian dysfunction, including menstrual irregularities, impaired ovarian reserve, and premature reproductive aging, yet effective therapeutic strategies to safeguard ovarian function against metabolic stress remain limited. Mesenchymal stem cells (MSCs) have emerged as pivotal regulators of tissue homeostasis, with their paracrine effects largely mediated by extracellular vesicles (EVs). Here, we demonstrate that menstrual blood-derived endometrial stem cell-EVs (MenSC-EVs) alleviate streptozotocin (STZ)-induced ovarian dysfunction and inhibit granulosa cells (GCs) ferroptosis by delivering HSPA5. Mechanistically, EV-associated HSPA5 restored AKT/mTOR signaling and was accompanied by reduced BECN1 phosphorylation, thereby preserving the SLC7A11/GPX4-associated antioxidant pathway. We further show that BECN1 directly interacts with SLC7A11, linking BECN1 signaling to regulation of the system Xc−/GPX4 antioxidant axis. MenSC-EVs preserved this antioxidant pathway and reduced lipid peroxidation in injured GCs. Collectively, these findings identify an HSPA5-dependent anti-ferroptotic mechanism through which MenSC-EVs ameliorate T1DM-associated ovarian dysfunction, supporting their potential as an ovarian-protective strategy under diabetic conditions. Download: Download high-res image (241KB) Download: Download full-size image
✓ 已验证
DOI
高影响因子
Redox Biology
·
2026
·
IF 16.2
Zitong Zhao,Ge Ge,Menghan Gong,Yi Liu,Liying Ma,Dongdong Zhang,Li Sun,Yongmei Song
Background Cisplatin resistance is a primary cause of treatment failure in ovarian cancer (OC), partly due to enhanced antioxidant defenses that counteract cisplatin-induced DNA damage and reactive oxygen species (ROS). Beyond the classic Glutathione Peroxidase 4 (GPX4) pathway, evidence suggests that non-canonical pathways like those mediated by Ferroptosis Suppressor Protein 1 (FSP1) may drive resistance. This study aims to elucidate how such alternative pathways facilitate resistance under cisplatin-induced ROS stress. Methods Ubiquitin Specific Peptidase 18 (USP18) was identified from a deubiquitination library. Protein/RNA interaction and m 6 A analyses revealed its regulation of downstream effectors Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and FSP1. The combination of cisplatin with the FSP1 inhibitor (iFSP1) was evaluated in vitro and in vivo models. Results Cisplatin-induced ROS upregulates the expression of the USP18 through the transcription factor c-JUN, establishing the ROS-c-JUN-USP18 signaling axis. This axis stabilizes the IGF2BP2 protein via USP18-mediated deubiquitination, which in turn enhances the stability of FSP1 mRNA in an m6A methylation-dependent manner, thereby driving the selective activation of the FSP1-mediated pathway over the canonical GPX4 pathway. The predictive efficacy of models derived from the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis was demonstrated by ROC curves and nomograms, confirming their utility in identifying patients with cisplatin-resistant OC. Importantly, the combination of iFSP1 with cisplatin produces a significant synergistic effect, effectively overcoming drug resistance in USP18-high tumors. Conclusion This study elucidates the mechanism by which the ROS-c-JUN-USP18-IGF2BP2-FSP1 axis regulates cisplatin resistance and proposes a novel iFSP1-cisplatin combination therapy, offering a promising new strategy for OC treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 15
Jingting Li,Sihan Wang,Fan Yang,Yang Guo,Xinyu Gao,Mingyu Nie,Zihan Zhou,Hao Xin,Fei Song,Changsong Dai,Zhaohui Wen
Background: Single-atom nanozymes (SAzymes) generally trigger catalytic reactions in situ within tumor cells, generating toxic reactive oxygen species (ROS) that induce cell death through oxidative stress, thereby achieving catalytic tumor therapy. However, therapeutic efficacy is often limited by insufficient ROS levels and intrinsic cellular antioxidant defenses. Results: This study developed a spherical mesoporous iron-based single-atom nanozyme (Fe-SAzyme) modified with polyethylene glycol (PEG) and (4-carboxybutyl)triphenylphosphonium bromide (TPP), achieving photothermal amplification of catalytic activities to deliver antitumor therapeutic effects. Fe-SAzyme exhibited triple enzyme-mimetic activities-peroxidase-like, glutathione peroxidase-like, and catalase-like activity. It simultaneously generated ROS and oxygen while oxidizing glutathione to oxidized glutathione. This elevation in ROS levels and weakening of antioxidant defenses disrupted intracellular redox homeostasis, ultimately triggering a process known as ferroptosis. Density functional theory (DFT) calculations revealed that Fe-SAzyme exhibited a low energy barrier for hydroxyl radical generation and possessed a viable cyclic catalytic pathway. Additionally, Fe-SAzyme-TPP exhibited exceptional photothermal conversion capabilities under second near-infrared (NIR-II) irradiation, enabling its use in photothermal therapy (PTT), while simultaneously enhancing catalytic activity and thereby significantly improving tumor treatment efficacy. In vitro and in vivo experiments demonstrated that PEG and TPP-modified Fe-SAzyme exhibited outstanding antitumor efficacy, along with enhanced biocompatibility and targeting capabilities. Under NIR-II irradiation, photothermal therapy synergized with catalytic activities, significantly amplifying tumor suppression effects. Conclusion: This study proposed a combined antitumor strategy based on iron-based SAzymes, utilizing photothermal amplification to enhance catalytic activities in conjunction with PTT, thereby achieving ferroptosis-based antitumor effects.
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Qiyu Zhu,Zhifa Wang,Lu Xia,Fengzhuo Zhou,Zhishuai Zhou,Junfang Sun,Yulu Li,Lunxu Wang,Yunhao Li,Liuyang Yan,Wei Mei,Qingling Yang,Mingliang Zhang,Wenrui Wang
Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options and poor prognosis, creating an urgent demand for novel strategies. Sonodynamic therapy (SDT) is a promising non-invasive approach, yet its clinical translation is restricted by low efficacy of traditional sonosensitizers and single-modal limitations. In this study, we constructed a zinc‑copper‑iron-based layered double hydroxide (ZnCuFe@LDHs) nanoplatform integrating SDT with synergistic ferroptosis and cuproptosis for targeted TNBC treatment. In vitro experiments with 4 T1 cells demonstrated efficient cellular internalization and lysosomal escape of ZnCuFe@LDHs. Under ultrasound stimulation, the nanoplatform generated abundant reactive oxygen species (ROS) and released Cu 2+ /Fe 3+ in response to the acidic tumor microenvironment (TME) and elevated intracellular glutathione (GSH). These events synergistically triggered ferroptosis by inactivating glutathione peroxidase 4 (GPX4) and accumulating lipid peroxide, while inducing cuproptosis through Cu 2+ overload, mitochondrial dysfunction, tricarboxylic acid cycle disruption and lipoylated dihydrolipoamide acetyltransferase (DLAT) oligomerization. Additionally, ZnCuFe@LDHs triggered immunogenic cell death (ICD) characterized by calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release, promoting dendritic cell maturation and antitumor immunity. In vivo studies using 4 T1 subcutaneous xenograft models confirmed significant tumor growth suppression by ZnCuFe@LDH and ultrasound, with no obvious systemic toxicity. Serum biochemical analysis and histological examination of major organs validated favorable biocompatibility. Collectively, ZnCuFe@LDHs achieves potent targeted antitumor efficacy via the integration of SDT, ferroptosis, cuproptosis, andimmunogenic cell death(ICD). This quadruple-modal synergistic strategy offers a safe and translational therapeutic option for TNBC.
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）