Nature Communications
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2025
·Vol. 16
·期 1
·1-14
·
IF 15.7
Tong Li,Wang Jie,Ma Yunjin,Wang Chunying,Fu Yue,Li Qi,Gao Chengjiang,Song Hui,Qin Ying,Zhao Chunyuan,Zhao Wei
Viruses rely on intracellular materials, including iron, to complete their life cycles and iron withholding may limit viral infections. However, the mechanisms through which viruses disrupt host iron homeostasis and the impact of intracellular iron on the host’s antiviral defense aren’t well studied. Here we show that viral infections facilitate the polyubiquitination and degradation of ferroportin (FPN1, the only cellular iron exporter) by upregulating the host E3 ubiquitin ligase DTX3L, leading to an elevation in cellular iron levels. Excessive ferrous iron suppresses type I IFN responses and autophagy by promoting TBK1 hydroxylation and STING carbonylation in macrophages. FPN1 deficiency suppresses host antiviral defense and facilitates viral replication in vitro and in vivo, while DTX3L deficiency has the opposite effect. These results reveal that viruses hijack host FPN1 to disrupt iron withholding and achieve immune escape, and suggest that iron homeostasis maintained by FPN1 is required for the optimal activation of TBK1- and STING-dependent antiviral responses.
研究领域:
微生物学
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免疫学
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生物化学
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分子生物学
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PubMed
高影响因子
Journal of Environmental Sciences
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2025
·
IF 6.3
Hongfei Hu,Guangji Wei,Hai Lan,Yang Feng,Shihua Luo,Yaqin Pang,Yanxin Huang,Huixiong Yuan,Huixin Peng,Wencheng Chen
The liver, a critical metabolic organ, is particularly vulnerable to damage upon aluminum exposure. However, the precise molecular mechanisms through which aluminum induces hepatotoxicity remain to be fully elucidated. This study aimed to investigate the adverse effects of aluminum exposure on mouse liver tissue. The results indicated that AlCl 3 exposure induced significant liver dysfunction, characterized by reduced adenosine triphosphate levels, elevated plasma alanine aminotransferase and aspartate aminotransferase. Histopathological analysis of liver tissue revealed marked histological damage, accompanied by substantial iron deposition. Further examinations demonstrated elevated hepatic levels of malondialdehyde, 4-hydroxynonenal, and reactive oxygen species, decreased levels of glutathione (GSH) and superoxide dismutase, increased levels of Oxidized glutathione (GSSG), and a reduced GSH/GSSG ratio. The mRNA and protein expression of ferroptosis-related molecules, including downregulated glutathione peroxidase 4 and solute carrier family 7 member 11, were significantly downregulated, while acyl-CoA synthetase long-chain family member 4, ferritin heavy chain 1, and iron regulatory protein 1 levels were significantly upregulated. Treatment with Ferrostatin-1 markedly ameliorated liver dysfunction and histopathological damage, attenuating signs of ferroptosis. These findings highlight the potential of ferroptosis-targeted therapies as a viable treatment strategy for aluminum exposure-induced hepatocyte injury.
研究领域:
毒理学
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肝脏病学
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分子生物学
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PubMed
高影响因子
PLoS Genetics
·
2025
·Vol. 21
·期 5
·e1011704
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IF 3.7
Zhiming Liu,Gang Du,Yi Chen,Haiyang Chen
The decline in adult stem cell performance is closely linked to tissue malfunction and the rising incidence of age-related diseases. To investigate the molecular basis of these impairments, our screening strategy identified reduced activity in the pantothenate/coenzyme A (CoA) pathway within aged ISCs. Furthermore, exogenous CoA supplementation restructured ISC metabolic pathways, reversing age-induced hyperproliferation and intestinal dysfunction, and thus extending Drosophila lifespan by curbing excessive iron accumulation in ISCs. These findings uncover a new mechanism of stem cell aging and propose that pantothenate and CoA could be potential therapeutic targets for treating age-related diseases and enhancing healthy aging in humans.
In our study, we explored the connection between the aging of adult stem cells and the rise of age-related diseases, uncovering a significant metabolic link. As stem cells age, a key metabolic pathway involving pantothenate and CoA becomes less active, leading to an accumulation of excess iron, which disrupts cellular function and contributes to the aging process. To counteract this decline, we added pantothenate and CoA to the aging stem cells, restoring their normal function, reducing iron buildup, and ultimately improving the health and lifespan of old fruit flies. This simple intervention not only highlights the potential of pantothenate and CoA as powerful tools to combat the effects of aging but also suggests broader implications for treating age-related diseases and promoting healthy aging in humans. Our findings provide a new perspective on the biology of aging and open up exciting new avenues for therapeutic interventions that could improve the quality of life for older individuals.
研究领域:
细胞生物学
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分子生物学
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衰老研究
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营养学
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PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Xiaowei Chai,Yuanying Jiang,Hui Lu,Xin Huang
Introduction: Candidiasis, mainly caused by Candida albicans, poses a serious threat to human health. The escalating drug resistance in C. albicans and the limited antifungal options highlight the critical need for novel therapeutic strategies.Methods: We evaluated 12 machine learning models on a self-constructed dataset with known anti-C. albicans activity. Based on their performance, the optimal model was selected to screen our separate in-house compound library with unknown anti-C. albicans activity for potential antifungal agents. The anti-C. albicans activity of the selected compounds was confirmed through in vitro drug susceptibility assays, hyphal growth assays, and biofilm formation assays. Through transcriptomics, proteomics, iron rescue experiments, CTC staining, JC-1 staining, DAPI staining, molecular docking, and molecular dynamics simulations, we elucidated the mechanism underlying the anti-C. albicans activity of the compound.Result: Among the evaluated machine learning models, the best predictive model was an ensemble learning model constructed from Random Forests and Categorical Boosting using soft voting. It predicts that Dp44mT exhibits potent anti-C. albicans activity. The in vitro tests further verified this finding that Dp44mT can inhibit planktonic growth, hyphal formation, and biofilm formation of C. albicans. Mechanistically, Dp44mT exerts antifungal activity by disrupting cellular iron homeostasis, leading to a collapse of mitochondrial membrane potential and ultimately causing apoptosis.Conclusion: This study presents a practical approach for predicting the antifungal activity of com-pounds using machine learning models and provides new insights into the development of antifungal compounds by disrupting iron homeostasis in C. albicans.
研究领域:
医学
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生物信息学
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PubMed
高影响因子
PLANT CELL AND ENVIRONMENT
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2021
·Vol. 44
·期 6
·1869-1884
·
IF 7.228
Wei-Jian Sun,Jiu-Cheng Zhang,Xing-Long Ji,Zi-Quan Feng,Xun Wang,Wen-Jing Huang,Chun-Xiang You,Xiao-Fei Wang,Yu-Jin Hao
Iron (Fe) is an essential element for plant growth, development and metabolism. Due to its lack of solubility and low bioavailability in soil, Fe levels are usually far below the optimum amount for most plants' growth and development. In apple production, excessive use of nitrogen fertilizer may cause iron chlorosis symptoms in the newly growing leaves, but the regulatory mechanisms underlying this phenomenon are unclear. In this study, low nitrate (NO 3 − , LN) application alleviated the symptoms of Fe deficiency and promoted lower rhizosphere pH, which was beneficial for root Fe acquisition. At the same time, LN treatment increased citrate and abscisic acid accumulation in roots, which promoted Fe transport from root to shoot and maintained Fe homeostasis. Moreover, qRT-PCR analysis showed that nitrate application caused differential expression of genes related to Fe uptake and transport, as well as transcriptional regulators. In summary, our data reveal that low nitrate alleviated Fe deficiency through multiple pathways, demonstrating a new option for minimizing Fe deficiency by regulating the balance between nutrients.
研究领域:
植物营养学
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分子生物学
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园艺学
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DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2025
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IF 11.3
Huaying Liu,Qisong Xing,Chenyu Zhu,Qineng Wang,Keding Lu,Song Guo,Zhijun Wu,Min Hu,Shao-Meng Li,Maosheng Yao
Endotoxin (lipopolysaccharide, LPS), widely distributed in the atmospheric environment with strong immunogenicity, is an important biological component of ambient particulate matter. However, whether LPS participates in atmospheric chemistry and how its biological health impacts change with the relevant processes are poorly understood. In this study, we employed the rat model to investigate the impact of ozone oxidation on the biological toxicity of LPS and used Fourier transform infrared spectroscopy and high-resolution electrospray mass spectrometry to study the underlying reaction mechanisms. The results show that the LPS can be oxidized by ozone and the resulting reactant greatly enhanced inflammatory anemia with a 177% capacity increase despite a minor influence on its immunogenicity. In contrast to the control, rats exposed to oxidized LPS were observed to release characteristic exhaled biomarkers, indicating that the formed reactant indeed altered the biological effects of LPS. Mechanistic investigation reveals that ozone oxidation of the hydroxyl group in the key toxic part of LPS, kdo2-lipid A, can cause dysregulation of iron homeostasis in rats, which is the mechanism of oxidized LPS-enhanced anemia. Unfortunately, these chemical structure changes and the resulting health impacts cannot be detected by the conventional LPS analysis method. This study highlights the changes in the toxicity of LPS and its health impacts when oxidized by ozone and the need to broadly consider the involvement of bioaerosol in atmospheric chemistry.
研究领域:
环境生物学
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毒理学
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医学
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PubMed
高影响因子
PATHOLOGY RESEARCH AND PRACTICE
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2020
·
IF 2.05
Jianfa Wu,Li Zhang,Suqin Wu,Xiaofang Yi,Zhou Liu
Background miR-194-5p has been associated with drug resistance in many cancers. However, the role of miR-194-5p in cisplatin resistance in ovarian cancer is still unclear. Materials and methods To study the role and mechanism of miR-194-5p in cisplatin resistance, qRT-PCR was performed to determine the expression of miR-194-5p and SLC40A1 in ovarian cancer. Cell Counting Kit-8 (CCK8) assay was used to analyse cell viability after cisplatin treatment . Dual-luciferase reporter gene assay was performed to examine the relationship between miR-194-5p and SLC40A1. The genes downstream of SLC40A1 were investigated through bioinformatics analysis. Results Compared to cisplatin-sensitive ovarian cancer cells , higher miR-194-5p expression and lower SLC40A1 expression were found in cisplatin-resistant ovarian cancer cells. Moreover, this study demonstrated that over-expression of miR-194-5p inhibited SLC40A1 expression, and knockdown of miR-194-5p promoted SLC40A1 expression. In addition, dual-luciferase reporter gene assay further confirmed the negative correlation between miR-194-5p and SLC40A1. Furthermore, we found that over-expression of miR-194-5p resulted in cisplatin resistance. When miR-194-5p and SLC40A1 were simultaneously up-regulated, cisplatin sensitivity increased, while down-regulation of miR-194-5p sensitised ovarian cancer cells to cisplatin. However, when miR-194-5p and SLC40A1 were simultaneously down-regulated, cisplatin sensitivity was decreased. These data suggested that miR-194-5p inhibited SLC40A1 expression to induce cisplatin resistance. In addition, bioinformatics analysis indicated a positive correlation of SLC40A1 with hephaestin (HEPH), and homeostatic iron regulator (HFE). However, we found that HEPH and HFE were associated with cisplatin resistance, suggesting that their role in drug resistance is induced by miR-194-5p/SLC40A1. Conclusion In conclusion, we found that miR-194-5p inhibited SLC40A1 expression to induce cisplatin resistance in ovarian cancer. This study suggests that miR-194-5p could be a potential therapeutic target and a prognostic biomarker for ovarian cancer, with important implications for future research.
研究领域:
肿瘤学
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分子生物学
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遗传学
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Wenli Guo,Jinjin Zhang,Xiaoqian Zhang,Quanzhong Ren,Guangzhe Zheng,Jianxin Zhang,Guoxing Nie
Cadmium (Cd) pollution is considered a pressing challenge to eco-environment and public health worldwide. Although it has been well-documented that Cd exhibits various adverse effects on aquatic animals, it is still largely unknown whether and how Cd at environmentally relevant concentrations affects iron metabolism . Here, we studied the effects of environmental Cd exposure (5 and 50 μg/L) on iron homeostasis and possible mechanisms in common carp. The data revealed that Cd elevated serum iron, transferrin saturation and iron deposition in livers and spleens, leading to the disruption of systemic iron homeostasis. Mechanistic investigations substantiated that Cd drove hemolysis by compromising the osmotic fragility and inducing defective morphology of erythrocytes. Cd concurrently exacerbated hepatic inflammatory responses, resulting in the activation of IL6-Stat3 signaling and subsequent hepcidin transcription. Notably, Cd elicited ferroptosis through increased iron burden and oxidative stress in livers. Taken together, our findings provide evidence and mechanistic insight that environmental Cd exposure could undermine iron homeostasis via erythrotoxicity and hepatotoxicity. Further investigation and ecological risk assessment of Cd and other pollutants on metabolism-related effects is warranted, especially under the realistic exposure scenarios.
研究领域:
环境科学
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毒理学
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水生生物学
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分子生物学
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PubMed
高影响因子
CANCER RESEARCH
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2025
·
IF 16.6
Zhou Hai-Meng,Liu Yi,Shi Feng,Qiu Hao-Wen,Li Le,Shu Qi-Peng,Liu Yu-Ying,Wang Bai-Qi,Gao Meng,Du Run-Lei,Ke Shao-Bo,Zhang Xiao-Dong
Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, plays a crucial role in colorectal cancer (CRC) progression and therapeutic response. The NRF2 pathway is one of the critical axes in ferroptosis regulation, which governs oxidative stress resistance and iron homeostasis through its downstream targets, including HMOX1, SLC7A11, and others. However, HMOX1 and SLC7A11 exhibit contrasting roles in ferroptosis, with HMOX1 promoting ferroptosis via iron accumulation and lipid peroxidation, while SLC7A11 inhibits ferroptosis by enhancing antioxidant defenses. Here, we identified CLK2 as a key regulator of the delicate balance of the opposing effects of HMOX1 and SLC7A11. CLK2 stabilized KEAP1 to suppress NRF2 activity, resulting in the downregulation of HMOX1 and SLC7A11. Simultaneously, CLK2 downregulated p53, thereby relieving p53-mediated repression of SLC7A11. The dual regulation by CLK2 disrupted the balance between HMOX1 and SLC7A11, leading to excessive activation of HMOX1 in the absence of CLK2, ultimately sensitizing CRC cells to ferroptosis. Additionally, CLK2 promoted CRC proliferation and tumorigenesis in patient-derived organoids, cell lines, and mouse models. Furthermore, combining the ferroptosis inducer Erastin with Oxaliplatin significantly enhanced anti-tumor efficacy in CLK2-deficient xenograft models. Together, this study establishes CLK2 as a critical inhibitor of ferroptosis via the KEAP1/NRF2/HMOX1 and p53/SLC7A11 axes, supporting its potential as a therapeutic target for CRC.
研究领域:
癌症生物学
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分子生物学
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细胞死亡
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信号转导
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肿瘤学
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药理学
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PubMed
高影响因子
ADVANCED MATERIALS
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2025
·
IF 26.8
Kai Xiang,Zhiying Xiao,Zheng Jing,Yuzhou Li,Meng Li,Zhikang Su,Ziyu Huang,Tianli Wu,Ping He,Yining Zhang,Fengyi Liu,Mingxing Ren,Sheng Yang
Cigarette smoke (CS) disrupts mitochondrial iron homeostasis, causing excess free iron to generate reactive oxygen species, leading to oxidative stress and impairing tissue repair. For smokers undergoing bone defect repair, achieving precise control over the balance between mitochondrial free iron and stored iron, while simultaneously enhancing endogenous iron homeostasis, poses a considerable challenge. This study introduces the iron balance dual-drive strategy (IBDS), which efficiently chelates mitochondrial free iron and promotes ferritin synthesis to create a FerritinBank for iron deposition, thus optimizing endogenous iron homeostasis. IBDS is delivered through an injectable, biodegradable iron-capturing hydrogel (SilMA/gelMA/DPT). The released DPT selectively targets and chelates free iron within mitochondria, modulating mitochondrial dynamics to restore their function. This action is complemented by the promotion of ferritin synthesis, which serves to bolster endogenous iron homeostasis and suppress ferroptosis. Transcriptomic sequencing and experimental data suggest that DPT corrects energy metabolism abnormalities and promotes mitochondrial macromolecule synthesis. In vivo studies confirm that the iron-capturing hydrogel significantly improves the healing of smoking-induced calvarial bone defects. This is the first report of nanoparticles promoting ferritin synthesis to build an endogenous iron reservoir, highlighting the potential of the IBDS strategy for bone regeneration in smokers and other iron-overload-related conditions.
研究领域:
医学
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生物材料学
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分子生物学
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DOI
PubMed
高影响因子
Antioxidants
·
2025
·Vol. 14
·期 10
·1178
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IF 6.6
Qianqian Li,Shaobo Yun,Xiaomin Ren,Sijie Wu,Jia Cheng,Xiaoyong Huang
The rapid emergence and global dissemination of colistin resistance pose a critical threat to public health by limiting therapeutic options against Gram-negative infections. In this study, we report that bakuchiol (BAK), a natural antioxidant meroterpenoid, significantly restores colistin (COL) efficacy against a range of clinically relevant Gram-negative pathogens, including colistin-resistant strains. The combination of BAK and COL reduced the minimum inhibitory concentrations (MICs) of colistin by 8- to 32-fold, indicating strong synergistic antibacterial activity. Mechanistic studies revealed that BAK disrupts bacterial iron homeostasis via chelation-mediated intracellular iron depletion and concurrently compromises membrane integrity through interaction with phospholipids. This dual action induces collapse of the proton motive force and severe metabolic dysfunction. Importantly, the BAK–COL combination exhibited no detectable toxicity and demonstrated potent in vivo efficacy in aGalleria mellonellainfection model. Furthermore, formulation with polyvinylpyrrolidone (PVP) markedly improved the solubility and sustained the synergistic effects of BAK over a broad concentration range. Our findings highlight the potential of bakuchiol as a novel antioxidant adjuvant and provide a promising combinatory strategy for overcoming multidrug-resistant bacterial infections.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-19
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IF 12.6
Du Chunhong,Wang Shuai,Cheng Yijie,Li Jie,Zhang Yufei,Li Zhuohao,Zhu Baolin,Wu Zhongming,Zhang Xinge,Zhou Lingyi
Pneumonia caused by Pseudomonas aeruginosa ( P. aeruginosa ) infection remains a formidable clinical challenge due to persistent biofilm formation and intrinsic antibiotic resistance, exacerbated by bacterial iron homeostasis that stabilizes biofilm architecture and neutralizes oxidative stress. Herein, we present Fe/TNT@NM, a biomimetic nanosonosensitizer activated by ultrasound (US) to dismantle biofilms through dual extracellular-intracellular mechanisms. The nanosonosensitizer features an iron-doped titanate nanotube (Fe/TNT) core encapsulated within a neutrophil membrane (NM). Under US irradiation, Fe/TNT@NM generates sonodynamic reactive oxygen species (ROS) extracellularly and enhances Fe 3+ release. These ions catalyze the Fenton reaction extracellularly to amplify chemodynamic effects and disrupt intracellular iron homeostasis, triggering bacterial ferroptosis. The NM coating enables immune evasion and biofilm-targeted delivery. This ultrasound-reinforced ferroptosis strategy synchronizes extracellular ROS storms with intracellular iron dyshomeostasis, achieving dual-action biofilm dismantling and eradication of drug-resistant P. aeruginosa . In a murine pneumonia model, Fe/TNT@NM suppresses biofilms and mitigates pulmonary injury. By converging biomimetic targeting, sonodynamic-chemodynamic cascades, and ultrasound-augmented ferroptosis, this nanosonosensitizer presents a paradigm-shifting approach to combat refractory biofilm infections and antibiotic resistance. Graphical
研究领域:
微生物学
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感染病学
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纳米医学
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呼吸病学
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免疫学
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分子生物学
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药理学
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PubMed
高影响因子
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