INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
You Zhou,You Wu,Rui Zhu
Background Septic acute kidney injury (S-AKI) is a major cause of acute kidney injury (AKI), but no effective therapies exist to prevent or treat it. Although KLF6 is linked to various pathophysiological processes, its exact role in S-AKI is not yet fully understood. Methods The role of KLF was investigated using both the mouse CLP model and in vitro systems. To identify the transcriptional targets regulated by KLF6, ChIP-qPCR and luciferase reporter assays were carried out. Biochemical and cellular techniques were employed to assess cellular injury and lipid peroxidation levels. The extent of ferroptosis was evaluated through transmission electron microscopy (TEM). Results KLF6 levels were significantly increased in a renal IRI model. Knockdown of KLF6 using AAV9 reduced kidney injury in both in vitro and in vivo models, while KLF6 overexpression aggravated injury. Overexpression of KLF6 promoted ferroptosis, whereas its knockdown reduced lipid peroxidation and ferroptosis. KLF6 regulates NCOA4 expression by binding to its promoter, controlling ferroptosis. Knockdown of NCOA4 in vitro alleviated ferroptosis and cellular damage caused by KLF6 overexpression. Pharmacological inhibition of KLF6 reduced kidney injury and ferroptosis in S-AKI mice. Conclusion Our study uncovered a previously unrecognized role for KLF6 in S-AKI. By facilitating NCOA4 transcription, KLF6 intensified ferroptosis, which, in turn, aggravated septic AKI.
研究领域:
肾脏病学
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分子生物学
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病理生理学
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细胞生物学
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转录调控
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DOI
PubMed
高影响因子
Autophagy
·
2025
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IF 14.3
Chenyu Luo,Haisheng Liang,Mintao Ji,Caiyong Ye,Yiping Lin,Yuhan Guo,Zhisen Zhang,Yinyin Shu,Xiaoni Jin,Shuangshuang Lu,Wanling Lu,Yazheng Dang,Hong Zhang,Bingyan Li,Guangming Zhou,Zengli Zhang,Lei Chang
Ferroptosis is an iron-dependent regulated form of cell death implicated in various diseases, including cancers, with its progression influenced by iron-dependent peroxidation of phospholipids and dysregulation of the redox system. Whereas the extracellular matrix of tumors provides mechanical cues influencing tumor initiation and progression, its impact on ferroptosis and its mechanisms remains largely unexplored. In this study, we reveal that heightened mechanical tension sensitizes cells to ferroptosis, whereas decreased mechanics confers resistance. Mechanistically, reduced mechanical tension reduces intracellular free iron levels by enhancing FTH1 protein expression. Additionally, low mechanics significantly diminishes NCOA4, pivotal in mediating FTH1 phase separation-induced ferritinophagy. Targeting NCOA4 effectively rescues ferroptosis susceptibility under low mechanical tension through modulation of FTH1 phase separation-driven autophagy. In conclusion, our findings demonstrate that mechanics regulates iron metabolism via NCOA4-FTH1 phase separation-mediated autophagy, thereby influencing ferroptosis sensitivity and offering promising therapeutic avenues for future exploration.
研究领域:
癌症生物学
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细胞代谢
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力学生物学
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分子生物学
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
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IF 4.8
Qiang-Ming Li,Shu-Zhen Wu,Xue-Qiang Zha,Dan-Dan Zang,Feng-Yun Zhang,Jian-Ping Luo
Ethnopharmacological relevance Ganoderma lucidum , a renowned tonic traditional Chinese medicine, is widely recognized for the exceptional activity in soothing nerves and nourishing the brain. It has been extensively employed to alleviate various neurological disorders, notably Parkinson’s disease (PD). Aim of the study To appraise the antiparkinsonian effect of GAA, the main bioactive constituent of G. lucidum, and clarify the molecular mechanism through the perspective of ferritinophagy-mediated dopaminergic neuron ferroptosis. Materials and methods PD mouse and cell models were established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP + ), respectively. Cell viability, behavioral tests and immunofluorescence analysis were performed to evaluate the neurotoxicity, motor dysfunction and dopaminergic loss, respectively. Biochemical assay kits were used to determine the levels of iron, lipid reactive oxygen species (ROS), malondialdehyde (MDA), total ROS and glutathione (GSH). Western blot and immunofluorescence were applied to detect the expressions of nuclear receptor co-activator 4 (NCOA4), ferritin heavy chain 1 (FTH1), p62 and LC3B. Additionally, NCOA4-overexpressing plasmid vector was constructed to verify the inhibitory effect of GAA on the neurotoxicity and ferroptosis-related parameters in PD models. Results GAA significantly mitigated MPP + /MPTP-induced neurotoxicity, motor dysfunction and dopaminergic neuron loss ( p ＜0.01 or p ＜0.05). In contrast to MPP + /MPTP treatment, GAA treatment decreased the levels of iron, MDA, lipid and total ROS, while increasing the GSH level. GAA also reduced the levels of NCOA4 and LC3B, and enhanced the expressions of FTH1 and p62 in PD models ( p ＜0.01 or p ＜0.05). However, the protective effect of GAA against the neurotoxicity, NCOA4-mediated ferritinophagy and ferroptosis in PD model was abolished by the overexpression of NCOA4 ( p ＜0.01). Conclusion GAA exerted a protective effect on PD, and this effect was achieved by suppressing dopaminergic neuron ferroptosis through the inhibition of NCOA4-mediated ferritinophagy.
研究领域:
神经药理学
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神经科学
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民族药理学
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分子生物学
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DOI
PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2025
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IF 8.2
Yuan Gao,Yian Deng,Wenjie Li,Junjie Wang,Mingze Liu,Hanchuan Dai
Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy contributes to maintain intracellular iron balance by regulating ferritin degradation, which is essential for redox homeostasis. CXC-motif chemokine receptor 3 (CXCR3) is involved in the regulation of oxidative stress and autophagy. However, its role in modulating intestinal oxidative damage through ferritinophagy and the gut microbiota remains unclear. In this study, the impact of CXCR3 inhibition on intestine oxidative damage, ferritinophagy, and the gut microbiota, as well as mitochondrial quality control was investigated both in vivo and in vitro. The results show that CXCR3 inhibition by AMG487 relieves Diquat-induced intestinal damage, enhances the expression of tight junction proteins, and enhances antioxidant capacity in mice. Simultaneously, CXCR3 inhibition improves gut microbiota composition, and promotes NCOA4-mediated ferritinophagy. Mechanistically, the effects of CXCR3 inhibition on ferritinophagy are explored in IPEC-J2 cells. Co-localization and interaction between CXCR3 and NCOA4 were observed. Downregulation of NCOA4-medicated ferritinophagy leads to increase the expression of tight junction proteins, reduces iron levels, restricts ROS accumulation, and enhances GPX4 expression. Moreover, CXCR3 suppression facilitates mitochondrial biogenesis and mitochondrial fusion, increases antioxidative capacity, as well as resulting in elevation of tight junction proteins. These findings suggest that CXCR3 inhibition reverses Diquat-induced intestinal oxidative damage, enhances mitochondrial function, and improves gut microbiota composition by elevating NCOA4-medicated ferritinophagy, which implies that CXCR3 may serve as a potential therapeutic intervention targeting iron metabolism for treating intestinal diseases.
研究领域:
医学
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细胞生物学
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微生物学
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DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2025
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IF 11.3
Jie Yang,Xue Wen,Yi-Tong Fu,Chao Li,Hai-Long Chang,Yao-Yao Lu,Xue-Ru Li,Rui-Feng Fan
Perfluorooctanoic acid (PFOA), a persistent organic pollutant, is widely distributed in the environment, leading to substantial bioaccumulation and posing significant public health concerns. The kidney is the primary target organ for PFOA, but a recognized mechanism remains unclear. The chicken embryo has been widely used as a maternal-independent model in toxicity studies. However, the toxic effects of PFOA in chicken embryo kidneys remain limited. In the present study, chicken embryos were injected with PFOA of different concentrations through the air cell to establish an in vivo model, and establish an in vitro model of chicken embryo kidney (CEK) cells for PFOA exposure. The results showed that PFOA promoted nephrotoxicity and induced ferroptosis in chicken embryo kidneys. Meanwhile, ferroptosis occurred in PFOA-treated CEK cells and was alleviated by ferroptosis inhibitor Ferrostatin-1 (Fer-1), Deferoxamine (DFO), and autophagy inhibitor Chloroquine (CQ). Further results suggested that PFOA activated nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy in chicken embryo kidneys and CEK cells. Mechanistically, PFOA diminished NCOA4 ubiquitination by reducing the expression of HECT and RLD domain containing E3 ubiquitin protein ligase 2 (HERC2), leading to increased NCOA4 expression and activated ferritinophagy. These findings indicated that PFOA induced ferroptosis via HERC2-regulated NCOA4 ubiquitination-dependent degradation in chicken embryo kidneys.
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高影响因子
Journal of Environmental Sciences
·
2026
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IF 6.5
Hongjing Zhao,Jiayin Yue,Yushan Song,Zizheng Wang,Mingwei Xing,Yu Wang
Arsenic induces time-dependent ferroptosis in zebrafish embryonic (ZF4) cells. • Ncoa4-mediated ferritinophagy plays a critical role in arsenic-induced ferroptosis. • Early arsenic exposure suppresses Ncoa4 and accumulates FTH1, delaying ferroptosis. • Late-phase arsenic activates Ncoa4, promoting ferritin degradation and iron release. • Melatonin alleviates arsenic-induced ferroptosis via Nrf2-dependent antioxidant pathway. Arsenic (As) is a widely distributed toxic pollutant worldwide, posing severe threats to the health of animals and plants. Transcriptomic analysis of zebrafish embryonic cells (ZF4) revealed that exposure to trivalent arsenic (arsenite, As 3+ ) significantly altered levels of FTH1 (ferritin heavy chain 1) and Ncoa4 (nuclear receptor coactivator 4), and was closely associated with the proteasome pathway. Based on these findings, we further investigated the mechanisms underlying As-induced cell death and potential intervention strategies. The results showed that As induced autophagic cell death. Ferroptosis occurred as a late event and was regulated by Ncoa4-mediated ferritinophagy: during the early stage of As exposure, FTH1 accumulated independently of Ncoa4 changes, likely as a protective iron-sequestering response; whereas in the late stage, Ncoa4 activation promoted ferritin degradation and iron release, ultimately triggering ferroptosis. Moreover, melatonin (1 mmol/L) significantly alleviated As-induced ferroptosis by strengthening cellular antioxidant capacity through activation of the Nrf2 signaling pathway. Overall, this study reveals a critical regulatory role of Ncoa4 in As-induced ferroptosis and provides experimental evidence supporting targeted intervention strategies for arsenic poisoning. Download: Download high-res image (284KB) Download: Download full-size image
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DOI
高影响因子
Cell Death Discovery
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2023
·Vol. 9
·期 1
·1-15
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IF 7
Li Hong-Ying,Wei Ting-Ting,Zhuang Miao,Tan Cheng-Ye,Xie Tian-Hua,Cai Jiping,Yao Yong,Zhu Lingpeng
Cellular senescence is a hallmark of aging and has been linked to age-related diseases. Age-related macular degeneration (AMD), the most common aging-related retinal disease, is prospectively associated with retinal pigment epithelial (RPE) senescence. However, the mechanism of RPE cell senescence remains unknown. In this study, tert-butyl hydroperoxide (TBH)-induced ARPE-19 cells and D-galactose-treated C57 mice were used to examine the cause of elevated iron in RPE cell senescence. Ferric ammonium citrate (FAC)-treated ARPE-19 cells and C57 mice were used to elucidated the mechanism of iron overload-induced RPE cell senescence. Molecular biology techniques for the assessment of iron metabolism, cellular senescence, autophagy, and mitochondrial function in vivo and in vitro. We found that iron level was increased during the senescence process. Ferritin, a major iron storage protein, is negatively correlated with intracellular iron levels and cell senescence. NCOA4, a cargo receptor for ferritinophagy, mediates degradation of ferritin and contributes to iron accumulation. Besides, we found that iron overload leads to mitochondrial dysfunction. As a result, mitochondrial DNA (mtDNA) is released from damaged mitochondria to cytoplasm. Cytoplasm mtDNA activates the cGAS-STING pathway and promotes inflammatory senescence-associated secretory phenotype (SASP) and cell senescence. Meanwhile, iron chelator Deferoxamine (DFO) significantly rescues RPE senescence and retinopathy induced by FAC or D-gal in mice. Taken together, these findings imply that iron derived from NCOA4-mediated ferritinophagy causes cellular senescence via the cGAS-STING pathway. Inhibiting iron accumulation may represent a promising therapeutic approach for age-related diseases such as AMD.
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Man Gao,Xue Yang,Xiuxia Wang,Tong Liu
Preeclampsia (PE), a pregnancy-specific disorder characterized by placental dysfunction and severe maternal-fetal complications, involves ferroptosis—an iron-dependent cell death driven by oxidative stress and lipid peroxidation. This study investigated the role of zinc-finger protein 36 (ZFP36) in regulating ferroptosis in trophoblast cells and its underlying mechanisms. In vitro , hypoxia/reoxygenation was applied to human trophoblast HTR-8/SVneo cells to model ischemic injury. ZFP36 was found to inhibit oxidative stress and ferroptosis by suppressing nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Mechanistically, ZFP36 binds to the 3′ untranslated regions (3′UTRs) of NCOA4 mRNA, promoting its degradation and thereby attenuating ferritinophagy. In vivo , lentiviral overexpression of ZFP36 in a rat model of PE (induced by reduced uteroplacental perfusion pressure) alleviated clinical symptoms and reduced NCOA4-mediated ferroptosis. Collectively, these results demonstrate that ZFP36 regulates ferroptosis by modulating NCOA4-dependent ferritinophagy, offering a potential therapeutic strategy for PE through targeting ferroptosis.
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高影响因子
Journal of Advanced Research
·
2024
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IF 11.4
Guiqin Huang,Yawen Cai,Menghui Ren,Xiaoyu Zhang,Yu Fu,Run Cheng,Yingdi Wang,Mingxing Miao,Lingpeng Zhu,Tianhua Yan
Introduction Triple-negative breast cancer (TNBC) is the primary cause of breast cancer-induced death in women. Literature has confirmed the benefits of Salidroside (Sal) in treating TNBC. However, the study about potential therapeutic targets and mechanisms of Sal-anchored TNBC remains limited. Objective This study was designed to explore the main targets and potential mechanisms of Sal against TNBC. Methods Network pharmacology, bioinformatics, and machine learning algorithm strategies were integrated to examine the role, potential targets, and mechanisms of the Sal act in TNBC. MDA-MB-231 cells and tumor-bearing nude mice were chosen for in vitro and in vivo experimentation. Cell viability and cytotoxicity were determined using CCK-8, LDH test, and Calcein-AM/PI staining. Antioxidant defense, lipid peroxidation, and iron metabolism were explored using glutathione, glutathione peroxidase, malondialdehyde (MDA), C11-BODIPY 581/591 probe, and FerroOrange dye. Glutathione peroxidase 4 (GPX4) or stearoyl-CoA desaturase 1 (SCD1) overexpression or nuclear receptor co-activator 4 (NCOA4) deficiency was performed to demonstrate the mechanism of Sal on TNBC. Results The prediction results confirmed that 22 ferroptosis-related genes were identified in Sal and TNBC, revealing that the potential mechanism of the Sal act on TNBC was linked with ferroptosis. Besides, these genes were mainly involved in the mTOR, PI3K/AKT, and autophagy signaling pathway by functional enrichment analysis. The in vitro validation results confirmed that Sal inhibited TNBC cell proliferation by modulating ferroptosis via elevation of intracellular Fe 2+ and lipid peroxidation. Mechanistically, Sal sensitized TNBC cells to ferroptosis by inhibiting the PI3K/AKT/mTOR axis, thereby suppressing SCD1-mediated lipogenesis of monounsaturated fatty acids to induce lipid peroxidation, additionally facilitating NCOA4-mediated ferritinophagy to increase intracellular Fe 2+ content. The GPX4 or SCD1 overexpression or NCOA4 deficiency results further supported our mechanistic studies. In vivo experimentation confirmed that Sal is vital for slowing down tumor growth by inducing ferroptosis. Conclusions Overall, this study elucidates TNBC pathogenesis closely linked to ferroptosis and identifies potential biomarkers in TNBC. Meanwhile, the study elucidates that Sal sensitizes TNBC to ferroptosis by SCD1-mediated lipogenesis and NCOA4-mediated ferritinophagy, regulated by PI3K/AKT/mTOR signaling pathways. Our findings provide a theoretical basis for applying Sal to treat TNBC.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2023
·
IF 6.1
Tongwen Huang,Ke Zhang,Junqiao Wang,Kaihong He,Xingtao Zhou,Shaoping Nie
Acrylamide (ACR) generated in carbohydrate-rich foods during thermal processing has been demonstrated to exhibit hepatotoxicity. As one of the most consumed flavonoids with diet, quercetin (QCT) possesses the ability to protect against ACR-induced toxicity, albeit its mechanism is unclear. Herein, we discovered that QCT alleviated ACR-induced elevated levels of reactive oxygen species (ROS), AST, and ALT in mice. RNA-seq analysis revealed that QCT reversed the ferroptosis signaling pathway upregulated by ACR. Subsequently, experiments indicated that QCT inhibited ACR-induced ferroptosis through the reduction of oxidative stress. With autophagy inhibitor chloroquine, we further confirmed that QCT suppressed ACR-induced ferroptosis by inhibiting oxidative stress-driven autophagy. Additionally, QCT specifically reacted with autophagic cargo receptor NCOA4, blocked the degradation of iron storage protein FTH1, and eventually downregulated the intracellular iron levels and the consequent ferroptosis. Collectively, our results presented a unique approach to alleviate ACR-induced liver injury by targeting ferroptosis with QCT.
研究领域:
毒理学
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药理学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2026
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IF 6.1
Chao Song,Xiaofei Wu,Chaoqi Chen,Baoxin Shen,Yuheng He,Fei Liu,Feng Chen,Zhijiang Fu,Zongchao Liu
Background: Intervertebral disc degeneration (IVDD), characterized by inflammation, cell death, and matrix dysregulation, involves ferroptosis and autophagy interactions, though the role of ferritinophagy remains unclear.Methods: This study integrated bioinformatics analysis of clinical transcriptomes, single-cell sequencing, and experimental models to identify molecular targets linking ferritinophagy to IVDD progression.Results: Multi-omics analysis revealed 10 ferroptosis-related hub genes (eg, NCOA4, TP53, SLC7A11) enriched in hypoxia, autophagy, and ferroptosis pathways. Single-cell profiling demonstrated dynamic shifts in nucleus pulposus cell (NPCs) phenotypes during degeneration, with increased pro-inflammatory monocyte/macrophage infiltration. Clinical and experimental validation showed elevated NCOA4 and ACSL4 (ferroptosis drivers) alongside reduced GPX4 and FSP1 (anti-ferroptotic factors) in degenerated discs. Mechanistically, NCOA4-mediated ferritinophagy promoted iron overload and lipid peroxidation by degrading ferritin, exacerbating oxidative damage. Resveratrol, a natural anti-inflammatory compound, mitigated IVDD in rat models by restoring disc height, suppressing IL1β, TNF-α, and IL6, and reversing ferroptosis/autophagy imbalance via NCOA4 downregulation. Cellular studies confirmed that resveratrol attenuated LPS-induced NPCs degeneration by blocking NCOA4-dependent ferritinophagy, reducing lipid peroxidation and cell death.Conclusion: This work identifies NCOA4 as a critical nexus coordinating ferroptosis-autophagy crosstalk in IVDD and establishes ferritinophagy as a novel pathological mechanism. Resveratrol’s therapeutic efficacy, mediated through multi-target modulation of inflammatory and iron homeostasis pathways, provides a promising strategy for IVDD treatment. The findings advance precision medicine approaches by elucidating ferritinophagy’s role and proposing resveratrol as a targeted intervention to disrupt this self-amplifying cycle of oxidative damage in disc degeneration.
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高影响因子
FASEB JOURNAL
·
2022
·Vol. 36
·期 12
·e22665
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IF 5.834
Yang Zheng,Tiejian Zhao,Jiaru Wang,Ruizhu Jiang,Jinbiao Huang,Weimin Li,Jiahui Wang
To explore the effect of curcumol on autophagy and ferroptosis of hepatic stellate cells, and to clarify the molecular mechanism of its anti-hepatic fibrosis. In the present study, we report that curcumol promotes the death of activated HSCs and reduces the deposition of extracellular matrix. Interestingly, curcumol treatment can trigger ferroptosis to eliminate activated HSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Curcumol promotes HSC autophagy, which may be the key mechanism for its induction of ferroptosis. It is worth noting that the upregulation of nuclear receptor coactivator 4 (NCOA4) may play a key molecular mechanism. NCOA4 mediates the release of iron ions and induces the occurrence of ferroptosis. Overall, curcumol promotes autophagy in hepatic stellate cells, mediates the degradation of NCOA4 and FTH1 complexes, releases iron ions, leads to iron overload, and induces ferroptosis, which may be an important mechanism for its anti-hepatic fibrosis effect.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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PubMed
高影响因子
危险品化学品经营许可证（带存储）