Human Cell
·
2025
·Vol. 39
·期 1
·27
·
IF 3.1
Xu Jianfeng,Lei Deng,Xu Peng,Wang Yuqi,Li Zhupeng,Wu Jiacheng,Feng Weizhong,Zhou Junqing
Esophageal cancer (EC) remains a highly aggressive malignancy with limited therapeutic success, partly due to heterogeneous responses to neoadjuvant chemotherapy (NAC). Tumor-derived exosomes and tumor-associated macrophages play critical roles in shaping the immunosuppressive tumor microenvironment, but their crosstalk in EC chemoresistance remains unclear. In this study, we identified tumor-derived exosomal miR-145-5p as a potential predictor of poor NAC response. Elevated exosomal miR-145-5p levels were associated with increased M2 macrophage infiltration and enhanced expression of M2 markers in EC tissues. Mechanistically, miR-145-5p promoted M2 macrophage polarization through the suppression of transferrin receptor (TFRC) and subsequent disruption of iron uptake. Consequently, these tumor-promoting M2-polarized macrophages enhanced EC cell proliferation, migration, invasion, and cisplatin resistance. In vivo, macrophages overexpressing miR-145-5p facilitated tumor growth and markedly weakened the therapeutic effects of cisplatin. Overall, our findings reveal that EC cells utilize exosomal miR-145-5p to remodel macrophages into a pro-tumorigenic phenotype through TFRC-dependent iron metabolic reprogramming, contributing to malignant progression and chemoresistance. Exosomal miR-145-5p may represent a promising biomarker for NAC response and a therapeutic target to improve treatment outcomes in EC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF TRACE ELEMENTS IN MEDICINE AND BIOLOGY
·
2025
·
IF 3.3
Siqi Hua,Shuangshuang Song,Chunhao Yang,Jingwen Xu,Zhonghua Li,Bo Zhu,Zichun Hua
Background Ferroptosis has emerged as a critical pathogenic mechanism in ulcerative colitis (UC). Metallothioneins (MTs), known for their redox regulatory functions, may protect against ferroptosis in UC. However, the underlying mechanisms are still unclear. Methods We conducted comprehensive investigations combining a bioinformatics analysis of a human UC dataset (GSE243625) with experimental validations using DSS-induced murine colitis models and RSL3-treated HCT116 human colon epithelial cells. Our experimental approaches included immunohistochemical analysis of MT2 expression, assessment of ferroptosis markers, evaluation of mitochondrial function, measurement of mitochondrial redox status and Fe 2+ , and profiling of protein expression. The therapeutic potential of ZnO nanoparticles was evaluated in vivo . Results Transcriptomic analysis revealed significant downregulation of all nine MT family members in UC patients, with the most pronounced suppression occurring in active disease. This finding was corroborated in murine models, which showed reduced colonic MT2 expression following DSS treatment. Cellular studies demonstrated that MT2A overexpression provides robust protection against RSL3-induced ferroptosis, evidenced by a reduction in lipid peroxidation, preservation of mitochondrial integrity, and decreased accumulation of mitochondrial reactive oxygen species. Mechanistically, MT2A modulated cellular iron homeostasis by downregulating transferrin receptor (Tfrc). Importantly, the oral administration of ZnO nanoparticles effectively restored MT2 expression, downregulated Tfrc, attenuated ferroptosis, and significantly alleviated colitis symptoms in vivo. Conclusions Our findings establish MT2A as a crucial regulator of ferroptosis in UC pathogenesis and identify ZnO nanoparticle-mediated MT2 induction and Tfrc downregulation as a promising therapeutic strategy. This study provides novel insights into the MT2A-ferroptosis axis and its potential translational applications for UC treatment.
研究领域:
胃肠病学
·
分子生物学
·
细胞生物学
·
氧化还原生物学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-17
·
IF 10.2
Wu Xinzhou,Jiao Zhouguang,Zhang Junying,Li Feng,Li Yuhua
Background Currently, high doses of cytarabine arabinoside (Ara-C)-based combined chemotherapy are commonly used in acute myeloid leukemia (AML) therapy, but severe adverse effects and poor suppression effects in leukemia cells limit the clinical therapeutic efficiency of Ara-C-based chemotherapy due to a lack of targeting selectivity. To improve the therapeutic effect of Ara-C in AML, here, since we confirmed that transferrin receptor 1 (TFRC) expression in AML cells was constant, we generated Ara-C@HFn by encapsulating free Ara-C into self-assembled heavy ferritin chain (HFn, the ligand of TFRC) nanocages.Results The analysis of clinically relevant data suggested that the high expression levels of TFRC from AML cells would not decrease significantly after treatment with Ara-C. Ara-C@HFn can be efficiently internalized by leukemia cells, showing stronger cytotoxic effects in vitro and reducing the burden of leukemia in AML mice more effectively in vivo than free Ara-C. Ara-C@HFn treatment showed no acute toxicity in visceral organs of mice. Moreover, the analysis of clinically relevant data also suggested that there are several drugs (such as tamibarotene and ABT199) that would not cause significant expression down-regulation of TFRC in AML cells (after treatment).Conclusion The above results suggested that TFRC can be used as a constant and effective target for drug targeting delivery of AML cells. Thus Ara-C@HFn treatment can become a safe and efficient strategy for AML therapy by specifically delivering Ara-C to AML cells. Besides, the HFn nanocages are promising for improving antineoplastic effect of other AML-related therapy drugs that do not cause downregulated expression of TFRC in AML cells.Graphical Abstract
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
血液学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Yuxi Guo,Xuemei Jia,Pengli Du,Jie Wang,Yao Du,Bolin Li,Yucong Xue,Jianming Jiang,Yanru Cai,Qian Yang
Ethnopharmacological relevance Xianglianhuazhuo formula (XLHZ) has a potential therapeutic effect on chronic atrophic gastritis (CAG). However, the specific molecular mechanism remains unclear. Aim of the study To evaluate the effect of XLHZ on CAG in vitro and in vivo and its potential mechanisms. Methods A rat model of CAG was established using a composite modeling method, and the pathological changes and ultrastructure of gastric mucosa were observed. YY1/miR-320a/TFRC and ferroptosis-related molecules were detected. An MNNG-induced gastric epithelial cell model was established in vitro to evaluate the inhibitory effect of XLHZ on cell ferroptosis by observing cell proliferation, migration, invasion, apoptosis, and molecules related to ferroptosis. The specific mechanism of action of XLHZ in treating CAG was elucidated by silencing or overexpression of targets. Results In vivo experiments showed that XLHZ could improve the pathological status and ultrastructure of gastric mucosa and inhibit ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway. The results in vitro demonstrated that transfection of miR-320a mimics inhibited cell proliferation, migration, and invasion while promoting cell apoptosis. MiR-320a targeted TFRC and inhibited ferroptosis. Overexpression of TFRC reversed the inhibitory effect of miR-320a overexpression on cell proliferation. The effect of XLHZ was consistent with that of miR-320a. YY1 targeted miR-320a, and its overexpression promoted ferroptosis. Conclusion XLHZ inhibited ferroptosis by regulating the YY1/miR-320a/TFRC signaling pathway, ultimately impeding the progression of CAG.
研究领域:
民族药理学
·
分子生物学
·
胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 24
·12671-12682
·
IF 5.396
Jing-yi Ren,Bo-wen Yin,Xiang Li,Si-qi Zhu,Jin-liang Deng,Yi-ting Sun,Zhen-ao Zhang,Zi-hao Guo,Huan-ting Pei,Fan Zhang,Rui-qiang Li,Feng-ge Chen,Yu-xia Ma
Objective: This study aimed to elucidate the pharmacological effects of sesamin (Ses) and its mechanism of action towards PM2.5-induced cardiovascular injuries. Method: Forty Sprague Dawley (SD) rats were randomly divided into five groups: a saline control group; a PM2.5 exposure group; and low-, middle-, and high-dose Ses pretreatment groups. The SD rats were pretreated with different concentrations of Ses for 21 days. Afterward, the rats were exposed to ambient PM2.5 by intratracheal instillation every other day for a total of three times. The levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and indicators related to oxidative responses, such as total superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), were measured in the blood and heart. The expression of ferroptosis-related proteins in heart tissues was determined via western blot and immunohistochemistry. Results: Ses pretreatment substantially ameliorated cardiovascular injuries in rats as evidenced by the decrease in the pathological score and collagen area. The decreased levels of SOD, GSH, and GSH-Px in the heart and serum were inhibited by Ses. In addition, Ses not only notably increased the activity of antioxidant enzymes but also reduced the levels of MDA, CK, LDH, CK-MB, IL-6, TNF-α, IL-1β, and IL-6. Furthermore, Ses pretreatment upregulated the expression levels of GPX4, SLC7A11, TFRC, and FPN1 and inhibited the expression levels of FTH1 and FTL. Conclusion: Ses pretreatment could ameliorate PM2.5-induced cardiovascular injuries perhaps by inhibiting ferroptosis. Therefore, Ses pretreatment may be a novel strategy for the prevention and treatment of PM2.5-induced cardiovascular injury.
研究领域:
药理学
·
心脏病学
·
毒理学
·
环境健康
✓ 已验证
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2026
·
IF 8.1
Hanfei Xie,Wumin Dai,Lu Sun,Wangang Gong,Tao Zhu,Yingli Zhang
Ovarian cancer (OV) is a highly lethal gynecological tumor, often developing platinum chemotherapy resistance and treatment failure. With their diverse and complex structures, natural products offer potential solutions to drug resistance. This study systematically examines chaetocin's effects on cisplatin-resistant OV cells and its underlying molecular mechanisms. We utilized a cell counting Kit-8, transwell assays, flow cytometry, immunohistochemistry, and western blotting to evaluate chaetocin's effects on cisplatin-resistant OV cells. Proteomic analysis and bioinformatics were utilized to identify the molecular targets of chaetocin, which were validated via cell transfection and co-immunoprecipitation. Additionally, a cisplatin-resistant OV xenograft model was developed for in vivo studies. Chaetocin suppressed the malignancy of cisplatin-resistant OV cells in a dose-dependent manner to suppress cell proliferation, impede cell migration and invasion, and induce both cell apoptosis and cell cycle arrest. Furthermore, in vivo studies showed that chaetocin inhibited tumor growth in a cisplatin-resistant OV xenograft model. In terms of mechanism, chaetocin induced ferroptosis in these cells, inhibiting TFRC ubiquitination and upregulating its expression by reducing the levels of cullin1 and its neddylation binding (cullin1-NEDD8). Our study uncovers a previously unrecognized mechanism: Chaetocin induces ferroptosis by inhibiting TFRC neddylation to upregulate its expression in OV. Unlike its known role as an SUV39H1 inhibitor, chaetocin functions through the neddylation-TFRC-ferroptosis axis, a pathway not previously linked to this compound. Moreover, while neddylation has recently been reported to regulate ferroptosis via SLC7A11, our study reveals an entirely distinct mechanism involving TFRC-mediated iron transport. This epigenetic regulation stabilizes TFRC, sensitizing resistant cells to ferroptosis, providing a dual-mechanistic insight not found in existing literature. By linking chaetocin's gene regulation to iron-dependent cell death, we offer new insights and potential therapies for cisplatin-resistant OV.
✓ 已验证
DOI
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Wang Ying,Zhang Qi,Liu Jiahui,Kuang Hongying,Feng Xiaoling
Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder among women of childbearing age and the leading cause of anovulatory infertility worldwide, with the death of granulosa cells implicated in its pathogenesis. However, the mechanisms underlying granulosa cell death remain unclear. Limited research has explored the association between GATA binding factor 1 (GATA1) and adverse pregnancy outcomes, yet its role in PCOS is still elusive. This study established an in vivo PCOS model via dehydroepiandrosterone administration in mice and used ovarian-like KGN cells to explore granulosa cell function. Results showed elevated ovarian GATA1 expression in PCOS mice. Functionally, GATA1 overexpression in KGN cells increased lipid reactive oxygen species, malondialdehyde, and iron, while reducing glutathione. Notably, all these effects of GATA1 were mitigated by a ferroptosis inhibitor Ferrostatin-1. Furthermore, GATA1 knockdown alleviated lipid peroxidation and iron overload in KGN cells induced by a ferroptosis inducer Erastin. Mechanistically, GATA1 directly bound the transferrin receptor (TFRC) promoter to enhance its transcription. Additionally, TFRC overexpression counteracted GATA1 knockdown’s protective effects against Erastin-induced ferroptosis. Collectively, GATA1 promotes granulosa cell ferroptosis via TFRC transcriptional activation, contributing to PCOS pathogenesis. GATA1 regulatory pathways may serve as potential therapeutic targets for PCOS.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EMBO REPORTS
·
2021
·Vol. 22
·期 2
·e51162
·
IF 8.807
Jia Song,Tongtong Liu,Yue Yin,Wei Zhao,Zhiqiang Lin,Yuxin Yin,Dan Lu,Fuping You
Although iron is required for cell proliferation, iron-dependent programmed cell death serves as a critical barrier to tumor growth and metastasis. Emerging evidence suggests that iron-mediated lipid oxidation also facilitates immune eradication of cancer. However, the regulatory mechanisms of iron metabolism in cancer remain unclear. Here we identify OTUD1 as the deubiquitinase of iron-responsive element-binding protein 2 (IREB2), selectively reduced in colorectal cancer. Clinically, downregulation of OTUD1 is highly correlated with poor outcome of cancer. Mechanistically, OTUD1 promotes transferrin receptor protein 1 (TFRC)-mediated iron transportation through deubiquitinating and stabilizing IREB2, leading to increased ROS generation and ferroptosis. Moreover, the presence of OTUD1 promotes the release of damage-associated molecular patterns (DAMPs), which in turn recruits the leukocytes and strengthens host immune response. Reciprocally, depletion of OTUD1 limits tumor-reactive T-cell accumulation and exacerbates colon cancer progression. Our data demonstrate that OTUD1 plays a stimulatory role in iron transportation and highlight the importance of OTUD1-IREB2-TFRC signaling axis in host antitumor immunity.
研究领域:
癌症生物学
·
免疫学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2026
·
IF 6.5
Caiyu Lian,Mingcheng Sun,Yue Li,Lin Wang
Cadmium (Cd) exposure triggers ferroptosis in renal tubular cells. • TFRC upregulation drives Cd‑induced ferroptosis by promoting iron influx. • HIF‑1α directly binds the TFRC promoter to transactivate its expression. • mPTP‑mediated calcium efflux activates CaMKII/HIF‑1α/TFRC axis. Cadmium (Cd) is a ubiquitous environmental pollutant and well-established nephrotoxicant primarily targeting renal proximal tubular cells. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a key mechanism in Cd‑induced kidney injury. Despite the central role of mitochondria in ferroptosis, the precise organellar events linking Cd exposure to ferroptotic execution remain obscure. Using Sprague‑Dawley rats and renal proximal tubular cells, we found that Cd exposure instigated ferroptosis, evidenced by iron overload, altered ferroptosis markers, lipid peroxidation, and typical mitochondrial morphology under transmission electron microscopy. Pharmacological inhibition of ferroptosis significantly attenuated Cd‑induced cellular damage, identifying ferroptosis as a critical driver. Mechanistically, Cd triggered opening of the mitochondrial permeability transition pore (mPTP), leading to mitochondrial calcium efflux and activation of calcium/calmodulin‑dependent protein kinase II (CaMKII). Activated CaMKII in turn increased hypoxia-inducible factor-1α (HIF-1α) transcription and promoted its nuclear accumulation. Notably, upregulated HIF‑1α directly bound to the promoter of transferrin receptor (TFRC) to stimulate expression of this key iron transport mediator, as confirmed by chromatin immunoprecipitation assay. Moreover, genetic knockdown of TFRC markedly attenuated Cd‑triggered ferroptosis and consequent cytotoxicity, establishing TFRC as a critical executioner of Cd‑evoked renal injury. Taken together, these findings delineate a novel signaling axis from mPTP‑mediated calcium efflux to HIF‑1α‑dependent TFRC transactivation that drives ferroptosis in Cd‑induced nephrotoxicity, offering a mechanistic basis for understanding and mitigating the renal health risks posed by environmental Cd exposure. Download: Download high-res image (405KB) Download: Download full-size image
✓ 已验证
产品关联
DOI
高影响因子
International Heart Journal
·
2026
·Vol. 67
·期 1
·87-97
·
IF 1.3
Zhuyuan Liu,Yanru He,Chunshu Hao
Myocardial ischemia-reperfusion injury (MI/RI) refers to the deterioration of cardiac function after restoring ischemic myocardium perfusion. Stem cell exosomes have produced unique advantages in treating MI/RI. However, the roles of exosomal microRNA-223-3p (miR-223-3p) from adipose-derived stem cells (ADSCs) on MI/RI are still unclear. This study aimed to investigate the effects of exosomal miR-223-3p from ADSCs on hypoxia/reoxygenation (H/R)-induced H9c2 cell injuries. Our findings indicated that the separated ADSC-derived exosomes (ADSC-Exo) were spherical, with a complete cell membrane, an average diameter of 110 nm, and CD9 and CD63 expression. ADSC-Exo increased the cell viability, proliferation, glutathione (GSH) level, and glutathione peroxidase 4 (GPX4) and miR-223-3p expression and decreased the apoptosis, reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ levels and acyl-CoA synthetase long chain family member 4 (ACSL4) and transferrin receptor (TFRC) expression of H9c2 cells. Overexpressing exosomal miR-223-3p from ADSCs further strengthened the effects of ADSC-Exo on H9c2 cells. Overexpressing TFRC in H9c2 cells effectively reversed the effects of miR-223-3p overexpressed ADSC-Exo on H9c2 cells. In addition, miR-223-3p targeted and negatively regulated TFRC. This study confirmed that exosomal miR-223-3p from ADSCs alleviated H/R-induced ferroptosis of H9c2 cells by inhibiting TFRC, providing a novel target and pathway for the clinical treatment of MI/RI.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2025
·
IF 3.3
Jing Cheng,Zhihan Liu,Haibo Liu,Chao Fang,Jun Li
Colorectal cancer (CRC) is one of the most prevalent malignant tumors worldwide, with its pathogenesis tightly linked to the regulation of cell death. Ferroptosis plays a pivotal role in the initiation, progression, and treatment of CRC. In our previous studies, we demonstrated that PPP2CA knockdown enhances the malignant phenotype of CRC cells while increasing their susceptibility to ferroptosis, albeit this latter effect frequently mitigates the malignant phenotype. The present study aims to further elucidate the regulatory mechanism underlying the association between PPP2CA and ferroptosis. Lentiviral-mediated PPP2CA knockdown was performed in CRC cell lines HCT116 and SW480 to establish stable PPP2CA-knockdown models, and PPP2CA gene expression in these models was verified. Colony formation assays and scratch wound healing assays were used to assess the proliferative and migratory capacities of CRC cells after PPP2CA knockdown. Additionally, CRC samples from The Cancer Genome Atlas (TCGA) database were analyzed via bioinformatics approaches to identify ferroptosis-related genes closely correlated with PPP2CA, with subsequent validation in model cells. The STRING database was employed to analyze the interaction networks between PPP2CA and target ferroptosis-related genes, predict potential signaling pathways via which PPP2CA regulates cellular ferroptosis, and validate these findings in model cells. Compared with the control group, HCT116 and SW480 cells in the PPP2CA-knockdown group exhibited significantly enhanced proliferative and migratory capacities. Bioinformatics analysis identified the top 10 most significant ferroptosis-related genes associated with PPP2CA. Validation in model cells showed that the expression levels of transferrin receptor (TFRC) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly upregulated. STRING analysis and in-model-cell validation indicated that increased mTOR phosphorylation subsequent to PPP2CA knockdown could upregulate the protein expression levels of transferrin receptor (TfR, encoded by the TFRC gene) and ACSL4, and this effect could be reversed by the mTOR inhibitor rapamycin. Thus, PPP2CA knockdown enhances the malignant phenotype of CRC cells, while potentially upregulating the expression of ferroptosis-related genes TFRC and ACSL4 via the mTOR signaling pathway, thereby increasing ferroptosis sensitivity.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症研究
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Tingwen Zhang,Ruihong Zou,Zheng Chen,Yawei Li,Xin Sun,Xialin Sun
Background Overuse of acetaminophen (APAP) can induce acute liver injury (ALI), and its mechanism is closely related to ferroptosis. 4′-O-β-D-glucosyl-5-O-methylvisamminol (5-O) is a natural coumarin glycoside with anti-inflammatory and antioxidant activities, but whether it can alleviate liver injury through intervention in ferroptosis and multi-dimensional mechanisms remains unclear. Purpose To explore whether 5-O can alleviate APAP-induced ALI through multiple mechanisms such as inhibiting ferroptosis, regulating inflammation, promoting lipid metabolism, and reshaping the intestinal microbiota . Methods Through in vitro and in vivo experiments, combined with CCK-8, Western blot, whole transcriptome sequencing, 16S rRNA sequencing, FMT and other techniques and methods, the mechanism of 5-O was evaluated from multiple levels such as cells, tissues, metabolism and flora. Results 5-O downregulated Tfrc/Slc39a14 in cells to reduce iron intake and upregulated Slc7a11/GPX4 to enhance antioxidant capacity. It reduced serum ALT/AST, alleviated liver tissue pathological damage, inhibited the expression of chemokines and inflammatory factors, and activated the PPARα-Fabp1/Me1 axis to promote lipid metabolism. Whole transcriptome analysis revealed that 5-O intervention was associated with upregulation of miR-30e-3p and downregulation of Tfrc, suggesting a potential role in modulating iron metabolism. Concurrently, the analysis indicated that 5-O treatment was linked to inhibition of the ferroptosis pathway and activation of the PPAR pathway. In addition, 5-O reshaped the intestinal microbiota, inhibited pro-inflammatory bacterial genera, and promoted the colonization of the probiotic Lactobacillus . Conclusion This study systematically clarified that the hepatoprotective effect of 5-O against APAP-induced liver injury is associated with a multi-dimensional network involving "ferroptosis-inflammation-metabolism-flora". The innovation lies in systematically elucidating the multi-faceted actions of a natural product, which may involve regulating ferroptosis through miR-30e-3p associated changes, cross-organ metabolic reprogramming, and microecological modulation. This work provides a candidate drug with multi-dimensional synergistic potential for the prevention and treatment of liver injury.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）