Browsing by Subject "Ferroptosis"

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    ACAT2 negatively modulated by FOXA2 suppresses ferroptosis to expedite the aggressive phenotypes of endometrial cancer cells
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Xiao, Xin; Huang, Tingyun; Chen, Bin; Zhu, Jinshu; Xiao, Qingbang; Bao, Yuxin
    Endometrial cancer (EC) remains a prevalent gynecological disease with a continuously rising incidence and fatality rate. Acyl coenzyme A: cholesterol acyltransferase 2 (ACAT2) has been commonly perceived as a tumor promoter in multiple human malignancies. This study was conducted to specify the role and mechanism of ACAT2 in EC, which has not been covered. The expression and prognostic significance of ACAT2 in EC samples were respectively analyzed by the ENCORI and Kaplan-Meier plotter databases. RT-qPCR and western blot examined ACAT2 and forkhead box protein A2 (FOXA2) expression in EC cells. The CCK-8 method, colony formation, and EdU staining assays detected cell proliferation. The cell cycle was detected by flow cytometry analysis. Wound healing and Transwell assays, respectively, estimated cell migration and invasion. The thiobarbituric acid reactive species (TBARS) method and BODIPY 581/591 C11 probe detected lipid peroxidation levels. FerroOrange staining estimated intracellular iron level. Western blot examined the expression of epithelial-mesenchymal transition (EMT) and ferroptosis-associated proteins. The human TFDB database predicted the binding of FOXA2 with the ACAT2 promoter, which was substantiated by ChIP and luciferase reporter assays. As a result, ACAT2 expression was increased in EC tissues and cells and associated with poor survival outcomes in EC patients. ACAT2 deletion might hinder EC cell proliferation, migration, invasion, and EMT while stimulating cell cycle arrest. Moreover, ACAT2 silencing promoted the ferroptosis of EC cells. Also, FOXA2 inactivated the transcription of ACAT2 through binding with the ACAT2 promoter. FOXA2 interference could promote the proliferation, migration, invasion, EMT, cell cycle, and inhibit the ferroptosis of ACAT2-silenced EC cells, which was partially reversed by the ferroptosis activator erastin. Conclusively, ACAT2 transcriptionally inactivated by FOXA2 might contribute to the malignant progression of EC via the inhibition of ferroptosis.
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    Differential expression of ferroptosis markers, circadian regulators, KLOTHO, and classical tumor suppressors in colorectal cancer according to tumor stage: Influence of age, anatomical location, and correlation patterns
    (2025) Cielo Garcia Montero; Oscar Fraile Martinez; Ana M. Minaya Bravo; Diego Liviu Boaru; Diego De Leon Oliva; Patricia De Castro Martinez; Majd N. Michael Alhaddadin; Silvestra Barrena Blázquez; Laura Lopez Gonzalez; Luis G. Guijarro; Natalio Garcia Honduvilla; Víctor Roberto Baena Romero; Carlos Daniel Padilla Ansala; Mar Royuela; María Del Val Toledo Lobo; Leonel Pekarek; Roberto Fernández Baillo Gallego de la Sacristana; Mauricio Hernández Fernández; Montserrat Chao Crecente; Melchor Alvarez-Mon; Raul Diaz-Pedrero; Miguel A. Ortega; Miguel A. Saez; Biología Celular e Histología
    Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with an incidence projected to rise significantly worldwide. While TNM staging remains the cornerstone of prognosis and treatment decisions, additional biomarkers are needed to enhance predictive accuracy and therapeutic targeting. Ferroptosis, an iron-dependent cell death pathway, has emerged as a key regulator of CRC progression and therapy resistance. Circadian rhythms, KLOTHO, and tumor suppressors, such as p53, CDKN1A (p21), and Rb, also play crucial roles in CRC biology. Integrating TNM staging with molecular markers and patient-specific variables offers a more precise, personalized approach to CRC management. In the present work, we analyze the histopathological expression of KLOTHO, ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian regulators (CLOCK, BMAL1, PER1, and PER2), and classical tumor suppressors (p53, p21, and Rb) in a cohort of 63 patients diagnosed with CRC. Besides, we have considered important clinical variables, like sex, age, and anatomical location, in our statistical analysis; correlation with the protein expression of these markers was also included for each stage (T1, T2, and T3). Our study reveals that advanced CRC stages (primarily T3) exhibit increased expression of ferroptosis markers (TFRC, ALOX5, ACSL4, and GPX4) and tumor suppressors (p53, p21, and Rb), alongside reduced histopathological detection of KLOTHO and circadian markers (BMAL1, CLOCK, PER1, and PER2) compared with earlier stages. Age, but not sex, influenced the expression of several markers. Tumor location also played a role, with right-sided CRCs showing significant stage-related differences in ferroptosis, tumor suppressor, and BMAL1, whereas left-sided tumors exhibited variations primarily in circadian markers (CLOCK, PER1, and PER2). Correlation analyses across tumor stages indicate dynamic shifts, with tumor suppressors maintaining positive associations with ferroptosis markers and anti-aging/circadian markers showing stage-dependent changes. Despite the inherent limitations of our study, these findings highlight the evolving biomarker landscape in CRC progression, although further research is needed to elucidate their clinical implications.
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    Electroacupuncture pretreatment inhibits ferroptosis and inflammation after middle cerebral artery occlusion in rats by activating Nrf2
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Pu, Yanpeng; Cheng, Jingyan; Wang, Zhenya; Zhang, Jingbo; Liang, Fajun; Zhang, Xianbao; Zheng, Zhijun; Yin, Miaomiao; Wang, Zhen
    Objective. Electroacupuncture (EA) pretreatment can effectively increase the tolerance of the brain to ischemic stroke. The mechanism of ischemic tolerance induced by EA is related to Nrf2, but its specific mechanism has not been elucidated. This paper was designed to explore the effect of EA pretreatment on brain injury and the related mechanisms. Methods. Rats were pretreated with EA before middle cerebral artery occlusion (MCAO) modeling. The symptoms of neurological deficit and the volume of cerebral infarction were measured. The levels of inflammatory factors, oxidative stress-related factors, LPO, ROS, and Fe2+ were evaluated by the corresponding kits. Cell apoptosis was determined through TUNEL staining. The mRNA expression of inflammatory factors was examined by RT-qPCR, and the protein expression of ferroptosis-related factors, pyroptosis-related proteins, Keap1, Nrf2, HO-1, and NQO1 by western blotting. Results. EA pretreatment improved the symptoms of neurological deficit and reduced the volume of cerebral infarction. EA pretreatment significantly inhibited oxidative stress, inflammatory response, ferroptosis, pyroptosis, and apoptosis in brain tissues of MCAO rats. Mechanistically, EA pretreatment could activate Nrf2 expression and reduce Keap1 expression. Conclusion. EA pretreatment reduced inflammation and oxidative stress and inhibited ferroptosis by activating Nrf2 expression, ultimately delaying the development of ischemic stroke.
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    ENO3 regulates ferroptosis by interaction with PKM2 to promote the progression of metabolic dysfunction-associated steatotic liver disease
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2026) Qian Hao; Xue Li; Jing Liu; Minghao Li; Baoding Li; Shengjuan Hu; Yanling Li; Xiaofei Li; Yuanyuan Tang; Fuliang Pan; Yanxia Liu; Min Niu; Zhenzi Cao; Biología Celular e Histología
    Background. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder characterized by excessive lipid accumulation in the liver. The glycolytic enzyme enolase 3 (ENO3) is reported to be most significantly elevated in the analysis of MASLD-related sequencing results based on the GEO database. However, the specific mechanism by which ENO3 regulates MASLD is not fully understood. Objective. To investigate the role and possible molecular mechanism of ENO3 in MASLD. Methods. The expression of ENO3 and PKM2 in the liver tissues of control and MASLD rats was detected by immunohistochemistry and western blot. In vitro studies involved treating THLE-2 cells with free fatty acids (FFA) and Ferrostatin-1 (Fer-1), as well as manipulating ENO3 expression via small interfering RNA (siRNA) and overexpression plasmids, and manipulating PKM2 expression via siRNA. Fat accumulation was assessed using Oil Red O staining and measurements of intracellular total cholesterol (TC) and triglycerides (TG). Ferroptosis markers, including SLC7A11, GPX4, Fe2+, and malondialdehyde (MDA), were evaluated. Protein-protein interactions between ENO3 and PKM2 were examined using co-immunoprecipitation (Co-IP) and immunofluorescence. Results. MASLD liver tissues exhibited significantly higher levels of ENO3 and PKM2. Silencing ENO3 in FFA-treated THLE-2 cells reduced fat accumulation, downregulated PKM2 expression, and decreased ferroptosis markers. Conversely, ENO3 overexpression promoted fat accumulation and ferroptosis, which were mitigated by Fer-1 or si-PKM2. Co-IP and immuno-fluorescence confirmed the physical interaction and co-localization of ENO3 and PKM2 in THLE-2 cells. Conclusions. ENO3 interacted with PKM2 to regulate ferroptosis and further promoted the progression of MASLD.
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    Ferroptosis-relevant mechanisms and biomarkers for therapeutic interventions in traumatic brain injury
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Rui, Tongyu; Li, Qianqian; Song, Shunchen; Gao, Yaxuan; Luo, Chengliang
    Traumatic brain injury (TBI) is one of the most significant health care problems worldwide, causing disability and death especially among young individuals. Although a large range of agents and therapies have been proved beneficial to lesions post- TBI to some extent, effective treatments have not been translated to the clinic. As a newly discovered form of iron-dependent regulated cell death, ferroptosis has been implicated in TBI. In this review, we update the current state of knowledge related to second injuries post-TBI, including ferroptosis, oxidative stress, mitochondrial dysfunction, neuroinflammation and so on, which often lead to chronic symptoms and long-term disability. This review systematically summarizes the latest progress in the pathophysiological mechanisms of TBI, with a focus on providing references for proposing new multi- molecular targets for comprehensive therapeutic strategies based on ferroptosis-relevant mechanisms. In addition, biomarkers are essential diagnostic and prognostic tools in TBI. Several biomarkers associated with the outcome of TBI have been listed in this article, such as Pde10a, MDA, UCH-L1, S100A9, S100B, ALDOC, ACSL4, MBP and F2-Isoprostane. Therefore, the understating of ferroptosis-relevant mechanisms and biomarkers may contribute to development of promising therapies for TBI clinical trials.
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    Ferroptosis: A key regulator and potential target for tissue injury
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Liu, Ruihan; Luo, Qing; Song, Guanbin
    The maintenance of iron homeostasis is essential for proper body function. A growing body of evidence suggests that iron imbalance is the common denominator in many tissue injuries, including acute, chronic, and reperfusion injuries. Ferroptosis, a novel form of programmed cell death due to metabolic abnormalities, has become increasingly recognized as an important process mediating the pathogenesis and progression of numerous tissue injuries, including cerebral, myocardial, lung, liver, kidney, and intestinal injuries. Therefore, a thorough understanding of the mechanisms involved in the regulation of ferroptosis might contribute to improvements in disease management. In this review, we summarize the importance of ferroptosis in various tissue injuries, discuss the potential targets of ferroptosis in the treatment of tissue injuries, and describe the current limitations and future directions of these novel treatment targets
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    Fortunellin attenuates sepsis-induced acute kidney injury by inhibiting inflammation and ferroptosis via the TLR4/NF-κB pathway
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Tianzhi, Liu; Yanmin, Zhang; Liu, Xiujuan; Zuo, Zhigang; Biología Celular e Histología
    Objective. To investigate the potential protective effect of fortunellin in sepsis-induced acute kidney injury (AKI) and its underlying mechanisms. Methods. Lipopolysaccharide (LPS)-treated human kidney proximal tubular epithelial (HK-2) cells were used as a cell model and sepsis-induced AKI was induced by cecal ligation and puncture (CLP) surgery in mice. Cell Counting Kit-8 (CCK8) assays and flow cytometry analysis were performed to examine the viability of HK-2 cells. Enzyme-linked immunosorbent assay (ELISA) was performed to investigate the content of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in vivo and in vitro. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), and free iron (Fe2+) were measured as indicators of ferroptosis. The phosphorylation levels of Interleukin-1 Receptor-Associated Kinase 4 (p-IRAK4), p65 (p-65), and inhibitor of kappa B alpha (p-IκBα) were detected by western blot as an indication of nuclear factor kappa-B (NF-κB) pathway activation. Results. Our cell and animal experiments revealed that fortunellin exhibits significant anti-inflammatory and cytoprotective properties. Fortunellin counteracted LPS-induced cellular damage in HK-2 cells, enhancing cell survival and suppressing the secretion of pro-inflammatory cytokines. Additionally, fortunellin demonstrated potent antioxidant effects, reducing MDA and Fe2+ levels while increasing SOD activity and GSH content. The protective effect of fortunellin was further corroborated in the mouse model of sepsis-induced AKI. Notably, fortunellin suppressed activation of the TLR4/NF-κB pathway in the AKI model, as evidenced by decreased levels of p-p65 and p-IκBα proteins. Conclusion. Fortunellin ameliorates inflammation and oxidative stress in sepsis-induced AKI, possibly through the modulation of the TLR4/NF-κB pathway. These findings suggest fortunellin's potential as a therapeutic agent for sepsis-associated AKI.
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    Galangin alleviates gastric mucosal injury in rats with chronic atrophic gastritis by reducing ferroptosis
    (Universidad de Murcia, Departamento de Histología e Histopatología, 2025) Yang Tian; Lu Min; Jiang Weiqiang; Jin Dandan; Sun Meiling; Mao Hua; Han Huixia; Biología Celular e Histología
    Objective. Chronic atrophic gastritis (CAG) is a precancerous lesion and is the first stage in a multistep precancerous cascade that can lead to gastric adenocarcinoma. This study aimed to reveal the role and mechanism of galangin in CAG. Methods. Rats were intragastrically administered a mixture of 2% sodium salicylate and 30% alcohol, forced to exercise, and fasted irregularly to establish CAG models. To explore the efficacy of galangin on CAG rats, we used Hericium erinaceus (HE) and omeprazole (Ome) as controls. The degree of gastric mucosal injury was assessed by H&E staining and immunohistochemistry. Perls staining and western blot analysis were used to assess iron content and enrichment of ferroptosis-related proteins. Reactive oxygen species and mitochondrial superoxide in the mucosa were visualized by probes. The morphology of cells was examined by transmission electron microscopy. Results. Our data showed that galangin treatment alleviated gastric mucosal damage and reduced ferroptosis in CAG rats, manifested as decreased iron content, iron transporters and storage proteins, decreased ROS and mitochondrial superoxide, and partially restored cellular morphology. Of note, galangin at a high concentration had better treatment efficacy than HE but lower than Ome. Conclusions. This study demonstrated that galangin reduced gastric mucosal injury in CAG rats by inhibiting ferroptosis. These findings provide a theoretical basis for its clinical application and broaden its potential applications
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    Protection of Qingfei Xieding prescription from idiopathic pulmonary fibrosis by regulating renin-angiotensin and ferroptosis in MLE-12 cells
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Sun, Lifang; He, Xinxin; Kong, Jiao; Zhou, Jianying
    Idiopathic pulmonary fibrosis (IPF) is a lifelong lung disease, but there is no specific drug for treatment. Qingfei Xieding prescription (QF) is active in the treatment of lung diseases. More comprehensive mechanisms over how QF exhibits anti-pulmonary fibrosis need to be elucidated. TGF-β was used to construct a pulmonary fibrosis cell model in vitro. Bleomycin was applied to induce a lung tissue fibrosis model in mice in vivo. Flow cytometry was used to detect cellular ROS and lipid oxidation levels. Cell substructure was observed by Transmission Electron Microscopy. ELISA was used to determine the levels of inflammatory factors. HE staining, Masson staining and immunohistochemistry were performed to evaluate the degree of fibrosis. Western Blot assay was used to determine the protein expressions of different molecules. In TGF-β-exposed lung epithelial MLE-12 cell model, α-SMA and Collagen I were significantly elevated and cell viability was reduced. QF treatment restored the cell viability decreased by exogenous TGF-β. Ferroptosis inducer Erastin administration could reverse the beneficial effects such as lipid oxidation and ROS reduction caused by QF treatment. QF was proven to inhibit ferroptosis and alleviated the process of IPF by activating ACE2 signal axis. In bleomycin induced IPF mice model, QF altered lung coefficient, body weight and the expression of inflammatory factors, which were prevented by ferroptosis activator Erastin. QF was demonstrated to affect the ACE2-ERK signaling axis in vivo. QF alleviated idiopathic pulmonary fibrosis by regulating renin-angiotensin through blocking ferroptosis. This research offers evidence for the potentiality of QF in clinical application for IPF therapy.
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    TRIM22 mechanism promoting KAT2A ubiquitination degradation to regulate ferroptosis in hepatocellular carcinoma cell invasion and metastasis
    (Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Wang, Wei; Chen, Xiaoshan; Wei, Wei; Biología Celular e Histología
    Objective. Hepatocellular carcinoma (HCC) is a highly fatal cancer. This study aims to investigate the underlying mechanism of tripartite motif-containing 22 (TRIM22) in HCC cell invasion and metastasis through the K (lysine) acetyltransferase 2A (KAT2A)/ glutathione peroxidase 4 (GPX4) axis. Methods. Human HCC cells BEL7405 were cultured in vitro and treated with MG-132, Ferrostain-1, pcDNA3.1-TRIM22, pcDNA3.1-KAT2A, or pcDNA3.1-NC. TRIM22-KAT2A interaction and KAT2A ubiquitination level, cell proliferation, invasion, migration, and histone H3 lysine 9 acetylation (H3K9ac) enrichment level on the GPX4 promoter were assessed by Co-IP, CCK-8, Transwell, and ChIP-qPCR assays. Mice were injected subcutaneously with Lv-oe-NC or Lv-oe-TRIM22 BEL7405 cells via the tail vein. Tumor proliferation and levels of TRIM22, KAT2A, GPX4, Fe2+, malondialdehyde (MDA), reactive oxygen species (ROS), and glutathione (GSH) in tissues and cells were evaluated by immunohistochemistry, RT-qPCR, western blot, and kits. Results. oe-TRIM22-treated BEL7405 cells exhibited increased TRIM22 expression, and abated KAT2A protein expression and malignant cell biological behaviors, which were partially reversed by upregulating KAT2A or suppressing ferroptosis. TRIM22 interacted with KAT2A, which was ubiquitinated to regulate GPX4 histone acetylation. TRIM22 overexpression elevated Fe2+, MDA, and ROS levels and cell death, and diminished GSH, GPX4, and H3K9ac enrichment levels, whereas further overexpression of KAT2A brought about opposite trends. TRIM22 suppressed HCC growth and metastasis by mediating ferroptosis through the KAT2A/GPX4 axis. Conclusions. TRIM22 promoted KAT2A ubiquitina-tion degradation to reduce H3K9ac enrichment levels in the GPX4 promoter region, and facilitated ferroptosis, thereby inhibiting HCC cell invasion and metastasis and in vivo growth and metastasis.