PHYTOMEDICINE
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2026
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IF 11.3
Si-Jia Jin,En-Guang Dou,Lei Wang,Lian-Wen Qi,Feng Wei,Lei Zhang
Background Abdominal aortic aneurysm (AAA) is a life-threatening vascular disorder characterized by progressive aortic wall degeneration, inflammation, and vascular smooth muscle cells (VSMCs) loss. Despite extensive research, no effective pharmacological treatment is currently available to prevent or halt AAA progression. Purpose This study aimed to discover effective therapeutic agents for AAA and identify potential natural compounds with pharmacological efficacy against the disease by targeting matrix metalloproteinase-2 (MMP2), a key enzyme involved in extracellular matrix degradation and aneurysm progression. Methods An integrated screening strategy combining cytotoxicity evaluation, high-content immunofluorescence imaging, and molecular docking was applied to an angiotensin II (Ang II)-stimulated rat aortic smooth muscle cells (RASMCs) model. A total of 138 natural products were systematically assessed. The anti-aneurysmal efficacy of the identified compound was further validated in both CaCl₂-induced and Ang II-infused ApoE -/- mouse models of AAA. Network pharmacology and metabolomic analyses were performed to elucidate the underlying molecular mechanisms. Results Salvianolic acid B (Sal B), a major polyphenol from Salvia miltiorrhiza, was identified as a potent anti‑AAA candidate. It suppressed aneurysm formation, reduced elastin degradation, and attenuated inflammatory infiltration in vivo, while preserving the contractile phenotype, lowering ROS, and inhibiting MMP activity in Ang II‑stimulated RASMCs in vitro. Mechanistically, Ang II suppresses NRF2, leading to downregulation of the System Xc⁻-GPX4 axis and promoting lipid peroxidation and VSMC ferroptosis. This ferroptosis then activates the AGE-RAGE pathway, amplifying inflammation and MMP‑driven matrix degradation. Sal B counteracts this cascade by restoring NRF2 activity, improving lipid metabolism, and inhibiting MMPs, thereby blocking ferroptosis‑initiated inflammation and preserving aortic integrity. Conclusion Salvianolic acid B exerts protective effects against AAA by attenuating oxidative stress, ferroptosis, and inflammation. These findings highlight Sal B as a promising natural therapeutic candidate for the prevention and treatment of abdominal aortic aneurysm.
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Science China-Chemistry
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2025
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IF 9.7
Gao Ji,Lu Song-Bo,Wang Fangliang,Zha Menglei,Li Kai
Ferroptosis, a form of unique cell death characterized by iron and iron-dependent accumulation of lipid peroxidation, has attracted increasing attention for cancer therapy. However, the antitumor efficacies of current small-molecule ferroptosis inducers are always not potent enough, and there is a debate over whether ferroptosis induces immunogenic or nonimmunogenic cell death. Guided by the pharmacophore concept, we rationally design a rhodanine-based small-molecule ferroptosis inducer, which can target the endoplasmic reticulum (ER) as a pivotal center for lipid metabolism. Metabolic and proteomic analyses suggest that the inducer causes dysregulation of cellular lipid metabolism, which can contribute to cell ferroptosis. In vivo results indicate that it triggers immunogenic cell death and activates the immune response to suppress tumor growth, accompanied by reversing the immunosuppressive tumor microenvironment and enhancing immunological memory. Furthermore, this inducer has an intrinsic photodynamic character that can further promote therapeutic efficacy with a single treatment. Specifically, the populations of CD8 + and CD4 + T cells in the spleen of tumor-bearing mice show a 3.2-fold and 2.6-fold increase upon treatment, respectively. Overall, this innovative approach has the potential to enhance antitumor therapies by exploiting the benefits of ferroptosis and immune activation, providing a working principle for further investigation of ferroptosis-based therapeutic strategies.
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Frontiers in Cell and Developmental Biology
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2025
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IF 4.3
Rui Wang,Jin-Feng Cui,Jing Lv,Jia-Lin Song,Yang-Yang Lu,Xiao-Juan Huang,Zhong-Kun Lin,Si-Yi Zhang,Sha-Sha Wang,Wen-Sheng Qiu
Introduction As a traditional medicine and food homologous plant, Perilla frutescens is widely cultivated in China, Japan, and Korea. According to the Compendium of Materia Medica , the leaves, stems, and seeds of perilla can all be used as medicine. Perilla essential oil has been used in traditional Chinese medicine since ancient times. It has been demonstrated that perillaldehyde (PAH), a primary composition of the essential oil extracted from perilla, can inhibit tumor growth through multiple mechanisms. However, the specific mechanisms by which PAH suppresses gastric cancer remain incompletely understood. Methods We performed in vitro experiments using three cell lines (AGS, HGC27, and MFC) to assess the effects of PAH on cell viability, proliferation, and migration of gastric cancer cells. Concurrently, we established a subcutaneous gastric tumor model in BALB/c nude mice for in vivo animal studies. Subsequently, oxidative stress was measured via fluorescence staining techniques (H 2 DCFDA, DHE, and JC-1). We then evaluated whether PAH induced ferroptosis in gastric cancer cells through FerroOrange staining, quantification of intracellular glutathione (GSH) and lipid peroxidation levels, and Western blotting. Finally, PAH was co-administered with the ferroptosis inhibitor Ferrostatin-1 (Fer-1) or the ferroptosis inducer RSL3, and relevant experiments were re-evaluated. Results In this study, PAH was proven to inhibit the growth of gastric cancer both in vivo and in vitro . It led to a reduction in mitochondrial membrane potential (MMP), an augmentation of the accumulation of reactive oxygen species (ROS), and an elevation of oxidative stress levels. Moreover, PAH decreased intracellular GSH levels while increasing intracellular lipid peroxidation and Fe 2+ levels. These effects indicate that PAH induces ferroptosis via inhibiting the system Xc (−)/GSH/GPX4 axis. Furthermore, PAH influenced the expression of proteins related to iron transport and storage and regulated ferroptosis via the P62-Keap1-Nrf2 pathway. When combined with the ferroptosis inducer RSL3, PAH could promote ferroptosis in gastric cancer. Discussion Our research suggests a potential therapeutic strategy in which PAH could be used to synergize with ferroptosis inducers for treating gastric cancer.
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FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Wenqi Qian,Xijun Chen,Liuqing Gu,Xiangxiang Lin,Jiawei Chen,Dongchen Xu,Hao Wang,Fucai Long,Qichuan ZhuGe,Peng Zhang,Haoqi Ni
An increasing body of evidence indicates that ferroptosis, characterized by lipid peroxidation (LPO), plays a significant role in the neurophysiological and pathological changes following traumatic brain injury (TBI). Herbacetin (HBT), primarily derived from Sedum plants, is hypothesized to possess strong antioxidant activity due to the presence of five phenolic hydroxyl groups in its structure, which may allow it to counteract ferroptosis after TBI, thereby offering a potential therapeutic approach for TBI treatment. In our study, we employed an erastin and RSL3-induced ferroptosis model using HT22 and PC12 cells. Our findings demonstrated that HBT significantly mitigates erastin-induced cell death by reducing reactive oxygen species (ROS) levels, LPO, and Fe 2+ accumulation. Moreover, HBT protected against changes in mitochondrial membrane potential and mitochondrial superoxide levels induced by erastin and RSL3. We further confirmed HBT’s ability to inhibit ferroptosis in the TBI mouse model. HBT reduced the levels of LPO and iron deposition in the tissue surrounding the injury site after TBI, protected neurons, and decreased microglial activation. Mechanistically, we showed that HBT upregulates hypoxia inducible factor-1α (Hif-1α) expression in both ferroptosis cells and the TBI animal model, which in turn leads to the upregulation of recombinant solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), thereby reducing ferroptosis. RNA-seq analysis and Hif-1α knockdown experiments in HT22 cells supported this conclusion. In conclusion, our findings provide a potential therapeutic basis for the clinical use of HBT in preventing neuronal ferroptosis following TBI.
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ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2025
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IF 11.3
Yanwei Wang,Jiahui Zhao,Yong Chen,Xuesong Liu,Tengfei Xu,Mingliang Fang
Chronic bisphenol exposure is a recognized disruptor of liver function, and although ferroptosis has been implicated, the underlying molecular mechanisms remain poorly defined. Here, integrative chemical proteomics and untargeted metabolomics were used to elucidate mechanisms of ferroptosis induced by bisphenol A (BPA) and bisphenol S (BPS) in hepatic cells. BPA elicited a pronounced ferroptotic phenotype, whereas BPS elicited a moderate phenotype in hepatocytes. Glutathione peroxidase 4 (GPX4) and pyruvate kinase M2 isoform (PKM2) were identified as critical targets, respectively. Validation through cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and molecular docking confirmed that BPA specifically binds to GPX4 (KD = 37.6 μM), while BPS exhibits moderate affinity for PKM2 (KD = 14.4 μM). Functional rescue experiments demonstrated that GPX4 overexpression effectively reversed BPA-induced ferroptosis and partially alleviated BPS-induced effects, whereas PKM2 overexpression specifically mitigated BPS-triggered cytotoxicity. Mechanistically, BPA inhibited GPX4 activity, impairing lipid peroxide detoxification and triggering ferroptosis; BPS suppressed PKM2, promoting glucose flux toward the methylglyoxal (MGO) pathway, depleting glutathione, and activating oxidative stress, thereby inducing ferroptosis indirectly. This study clarifies bisphenol-induced ferroptosis via target heterogeneity, providing mechanistic insights that may inform future safety evaluations.
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Frontiers in Pharmacology
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2025
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IF 4.8
Wenbin Ji,Yanbin Zhang,Wenhao Ji,Hui Zhang,Biao Qin,Xiao-Liang Xing,Zaiqi Zhang
Introduction: Pomolic acid (PA), a bioactive compound derived from Potentilla freyniana Bornm., is used palliatively for non-small cell lung cancer (NSCLC) in China’s Dongzu region, with some reports of clinical efficacy. However, the specific underlying molecular mechanisms remain unclear. This study aimed to identify the core targets of PA and explore its function and potential mechanisms in NSCLC.Methods: Network pharmacological analysis was utilized to identify the core targets of PA. In vitro functional studies were performed using NSCLC cells to investigate PA’s effects on cell death and proliferation. Assays were conducted to measure hallmarks of ferroptosis, including glutathione (GSH) depletion, iron (Fe2+)-dependent lipid peroxidation, and elevated reactive oxygen species (ROS) levels. Protein expression levels of key anti-ferroptotic factors (SLC40A1, SLC7A11, GPX4) and pro-ferroptotic proteins (ACSL4, HO-1) were assessed. Quantitative PCR (qPCR) was used to determine mRNA expression levels of genes negatively regulating ferroptosis (GPX4, SLC7A11, NRF2).Results: PA effectively induced cell death and inhibited proliferation in NSCLC cells. Characteristic hallmarks of ferroptosis were observed, including GSH depletion, Fe2+-dependent lipid peroxidation, and increased ROS levels. Protein expression levels of SLC40A1, SLC7A11, and GPX4 were significantly downregulated, while ACSL4 and HO-1 were markedly upregulated. mRNA expression levels of GPX4, SLC7A11, and NRF2 were also significantly reduced.Discussion: These findings suggest that PA exerts its anticancer effects primarily through ferroptosis induction. The observed modulation of key ferroptosis-related proteins and genes supports this mechanism. Therefore, PA may serve as a promising therapeutic agent for NSCLC treatment.
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MOLECULAR CARCINOGENESIS
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2024
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IF 3
Zhanbo Sun,Lixian Liu,Hongyuan Liang,Lingyun Zhang
Hepatocellular carcinoma (HCC) is a common malignancy worldwide. Herein, we investigated the role of nicotinamide mononucleotide (NMN) in HCC progression. HCC cells were treated with NMN (125, 250, and 500 μM), and then nicotinamide adenine dinucleotide (NAD + ) and NADH levels in HCC cells were measured to calculate NAD + /NADH ratio. Cell proliferation, apoptosis, autophagy and ferroptosis were determined. AMPK was knocked down to confirm the involvement of AMPK/mTOR signaling. Furthermore, tumor-inhibitory effect of NMN was investigated in xenograft models. Exposure to NMN dose-dependently increased NAD + level and NAD + /NADH ratio in HCC cells. After NMN treatment, cell proliferation was inhibited, whereas apoptosis was enhanced in both cell lines. Additionally, NMN dose-dependently enhanced autophagy/ferroptosis and activated AMPK/mTOR pathway in HCC cells. AMPK knockdown partially rescued the effects of NMN in vitro. Furthermore, NMN treatment restrained tumor growth in nude mice, activated autophagy/ferroptosis, and promoted apoptosis and necrosis in tumor tissues. The results indicate that NMN inhibits HCC progression by inducing autophagy and ferroptosis via AMPK/mTOR signaling. NMN may serve as a promising agent for HCC treatment.
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LIFE SCIENCES
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2024
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IF 5.2
Qiuwen Fei,Jian Zhang,Liangqiong Chen,Manqi Shi,Qinglan Wang,Feifan Xu,Jiahai Shi,Yongwei Qin
Background Mycobacterium tuberculosis infection triggers various forms of host cell death, including ferroptosis in lung epithelial cells; YY1, a critical transcription factor, plays a pivotal role in regulating ferroptosis, however, the underlying mechanisms are not fully understood. Methods To investigate Mycobacterium marinum ( M.marinum )infection in lung epithelial cells A549 and H1299, we utilized flow cytometry to evaluate cell death and measure reactive oxygen species (ROS). Colony-forming unit (CFU) assays determined the intracellular bacterial load. Ferroptosis was analyzed using a specific detection kit to measure malondialdehyde (MDA) and glutathione (GSH) levels. The interaction between the transcription factor YY1 and the iNOS promoter was assessed through a dual-luciferase reporter assay. Results M.marinum induced ferroptosis in lung epithelial cells through invasion. This effect is most pronounced at 8 h of infection and decreases over time but increased with a higher multiplicity of infection (MOI). YY1 knockdown decreases the expression of SLC7A11 and GPX4, attenuates cellular ferroptosis, while YY1 overexpression has the opposite phenomenon, enhancing the expression of bactericidal molecules such as iNOS and MPEG1, thereby markedly reducing the intracellular bacterial load. We identified substantial binding of YY1 to the iNOS promoter region (−655 to −1018 bp), enhancing mycobactericidal activity in YY1-overexpressing cells. Conclusions Our study demonstrates that YY1 inhibits ferroptosis induced by Mycobacterium marinum infection and reduces intracellular bacterial proliferation in lung epithelial cells. These findings provide a crucial basis for developing anti-tuberculosis therapies that target YY1 modulation, potentially offering new clinical avenues for the treatment of tuberculosis.
研究领域:
微生物学
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细胞生物学
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传染病学
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药理学
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Xinrui Yan,Linfeng Ma,Jing Ren,Binyan Chen,Wenxuan Song,Yu Dong,Xiaojiao Li,Yingjie Guo
Valproic acid (VPA), a widely used antiepileptic drug, often induces hepatic steatosis during long-term treatment, though the underlying mechanisms remain incompletely understood. In our study, epileptic patients with abnormal liver function exhibited significantly elevated levels of homocysteine (Hcy) and glutamate (Glu) compared to those with normal liver function. Moreover, Hcy and Glu levels were positively correlated with markers of lipid accumulation and oxidative stress. Similar elevations in Hcy and Glu were observed in VPA-treated mice and hepatocyte models (HepG2, AML12), suggesting that disrupted Hcy/Glu homeostasis may be a hallmark of VPA-induced hepatic steatosis. Further in vitro experiments demonstrated that treatment with either Hcy or Glu not only increased lipid accumulation but also triggered ferroptosis, as indicated by Fe 2+ overload, suppression of the GSH-GPX4 axis, and ACSL4-mediated lipid peroxidation. These effects were attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1), confirming the contribution of ferroptosis to Hcy/Glu-induced hepatotoxicity. Additional investigations revealed that VPA promotes Hcy accumulation by downregulating its catabolic enzymes (MTR, CBS, CTH), while enhancing Glu accumulation through upregulation of its synthetic enzymes (ALDH4A1, GLS) and repression of the catabolic enzyme GLUL, both in vivo and in vitro . The alterations in MTR, CBS, ALDH4A1, and GLS levels were shown to depend on HDAC1, as demonstrated using HDAC1 knockdown and overexpression systems in HepG2 cells. In summary, VPA disrupts Hcy/Glu homeostasis via HDAC1, leading to ferroptosis and subsequent hepatic steatosis. These findings highlight the HDAC1-Hcy/Glu-ferroptosis axis as a promising therapeutic target for mitigating VPA-induced hepatotoxicity.
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ADVANCED MATERIALS
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2026
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IF 29.1
Zekai Zhuang,Renlu Han,Yafei Hou,Qixiong Zhang,Jiancheng Yu,Na Li,Geng Wang,Jie Fu,Zhaozheng Deng,Hongwei Song,Yifei Qi,Keqi Tang
Ultrasound (US) induced piezoelectric catalytic therapy is an emerging cancer treatment method. However, the development and optimization of piezoelectric catalyst remain the major challenge. Herein, we have converted the classical dielectric material CaCu 3 Ti 4 O 12 (CCTO) into an efficient piezoelectric material through oxygen vacancy (V O ) engineering, enabling piezoelectric catalytic-driven cascade tumor therapy. The introduction of V O results in strong polarization and a robust piezoelectric coefficient. Density functional theory (DFT) calculations reveal that V O acts as an electron trap to suppress the recombination of electron and hole, enhancing the catalytic efficiency. The piezoelectric effect can “open” the cell membrane, facilitating the materials influx and triggering reactive oxygen species (ROS) storm. Meanwhile, the cavitation effect of US and tumor cell over-expressed glutathione (GSH) accelerate Cu and Ca release, causing intracellular ions overload. ROS and Ca ions damage mitochondria to evoke apoptosis, which accordingly shuts down the Cu + outflow pathway and expedites cuproptosis. Moreover, ROS and GSH depletion triggers ferroptosis. This process establishes a positive feedback loop mechanism. Transcriptome sequencing confirms the activation of cell death-related pathways. This study represents the first paradigm to create piezoelectricity through V O in CCTO for tumor therapy, advancing the applications of quadruple perovskites in tumor treatment.
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INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY
·
2026
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IF 3.7
Wen Zhang,Huang Lin,Ziqin Xiao,Dongxu Shen,Dingguo Xia,Zhiyong Qiu,Xuelian Zhang,Qiaoling Zhao
Trichlorfon (TCF), an organophosphorus pesticide, has long been used in agriculture as an insecticide for crop protection. However, its residual presence has caused significant economic losses to the sericulture industry, hindering the development of Bombyx mori ( B . mori ) farming. Although previous studies have investigated the toxicity of TCF to silkworms, the detailed toxic effects and molecular mechanisms remain poorly understood. In this study, the potential molecular targets and mechanisms of TCF-induced injury in silkworms were investigated in vivo and in vitro by combining RNA sequencing, qRT-PCR and other techniques. It is found that TCF exposure leads to damage of growth and development in silkworms, as evidenced by reduced body weight, increased mortality, and decline of cluster, cocooning, pupation and egg production. Further RNA sequencing analysis identified several differentially expressed genes, particularly LOC101744260 , as well as altered pathways, notably the glutamine metabolism pathway—both of which are closely associated with ferroptosis. In vivo and in vitro experiments have confirmed that the expression levels of ferroptosis-related genes, including Fer HCH , Fer 2LCH , Keap1 , Tf , Gtpx and SOD1 exhibited significant changes in expression levels. These changes are accompanied by elevated intracellular Fe 2+ and Fe 3+ levels and oxidative stress. Moreover, N-acetylcysteine (NAC) treatment partially reverses TCF-induced growth and developmental impairments at the individual and cellular levels. Taken together, these results indicate for the first time that TCF exposure induces damage of growth and development in silkworms by activating the ferroptosis pathway. This study provides a new insight into the toxic mechanisms of TCF in silkworms and offers a theoretical basis for the prevention and control of pesticide pollution in silkworms industry.
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DRUG DELIVERY
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2022
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IF 6.819
Ying Zhou,Chong-Yang Cai,Cheng Wang,Guo-Ming Hu,Yu-Ting Li,Meng-Jiao Han,Shen Hu,Pu Cheng
Skin infection is a major health issue that usually is caused by the continuous proliferation of bacteria in wounds. With the abuse of antibiotics worldwide, the battle against skin infection is becoming more and more difficult. Therefore, the development of new ways with different antibacterial mechanisms to current antibiotics is urgently needed. Inspired by the powerful inhibition of ferroptosis used in cancer therapy, here in our study, ferric-loaded lipid nanoparticles (Fe-LNPs) with unform size (∼130 nm) and surface charge (∼12 mV) were constructed and found to effectively inhibit the growth of both Gram positive (Staphylococcus aureus, S. aureus) and negative (Escherichia coli, E. coli) strains, possibly due to induction of ferroptosis-like cell death mechanisms. Most importantly, Fe-LNPs can also effectively inhibit the proliferation of S. aureus in a skin infection model and promote the healing of wounds. The Fe-LNPs can be applied as a powerful antibacterial formulation for future application in clinic.
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危险品化学品经营许可证（带存储）