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A tRNA-derived fragment tiRNA-Met-CAT-002 induced by myocardial ischemia/reperfusion injury inhibits cardiomyocyte autophagy by regulating Bnip3 心肌缺血/再灌注损伤诱导的trna衍生片段tiRNA-Met-CAT-002通过调节Bnip3抑制心肌细胞自噬
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-22 DOI: 10.1016/j.yexcr.2025.114809
Lang Deng , Yawen Weng , Jiahui Lin , Lingfeng Zhong , Zhixuan Tang , Shuang Lin , Weijian Huang , Zhenfeng Cheng , Kongjie Lu , Bozhi Ye
Myocardial ischemia/reperfusion (I/R) injury is a significant contributor to the development of heart failure. This study investigates the differential expression of tRNA-derived small RNAs (tsRNAs) during I/R and explores their potential functional implications. Through tRF & tiRNA sequencing, we identified 115 tsRNAs exhibiting significant changes in expression following I/R. Notably, tiRNA-Met-CAT-002 was found to be upregulated via the hypoxia/hypoxia-inducible factor 1 subunit α (HIF1α)/angiogenin (ANG) signaling axis. Our findings suggest that Bnip3 represents a crucial target for tiRNA-Met-CAT-002. Mechanistically, mimics of tiRNA-Met-CAT-002 reduced Bnip3 protein expression by directly targeting the 3′ untranslated region (UTR) of its mRNA in a manner resembling microRNA activity. Furthermore, tiRNA-Met-CAT-002 was observed to decrease autophagy levels while enhancing cell viability under hypoxia/reoxygenation (H/R) conditions. In conclusion, this study underscores the substantial role of tsRNAs in the pathophysiology of I/R injury, with tiRNA-Met-CAT-002 potentially serving as a protective factor by attenuating autophagy levels.
心肌缺血/再灌注(I/R)损伤是心衰发生的重要因素。本研究研究了trna衍生的小rna (tsrna)在I/R过程中的差异表达,并探讨了其潜在的功能意义。通过tRF &; tiRNA测序,我们鉴定出115种tsrna在I/R后表现出显著的表达变化。值得注意的是,tiRNA-Met-CAT-002通过缺氧/缺氧诱导因子1亚单位α (HIF1α)/血管生成素(ANG)信号轴被发现上调。我们的研究结果表明Bnip3是tiRNA-Met-CAT-002的关键靶点。在机制上,模拟tiRNA-Met-CAT-002通过直接靶向其mRNA的3 '非翻译区(UTR),以类似于microRNA活性的方式降低Bnip3蛋白的表达。此外,在缺氧/再氧化(H/R)条件下,观察到tiRNA-Met-CAT-002可以降低自噬水平,同时提高细胞活力。总之,本研究强调了tsRNAs在I/R损伤病理生理中的重要作用,其中tiRNA-Met-CAT-002可能通过降低自噬水平作为一种保护因子。
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引用次数: 0
Developmental delay in DCP2l(3)tb of Drosophila melanogaster is due to disruption in the regulation of ecdysone signaling 黑腹果蝇dcp21 (3)tb的发育延迟是由于蜕皮激素信号调节的中断。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-22 DOI: 10.1016/j.yexcr.2025.114808
Govind R. Chaudhary, Vaishali Yadav, Jagat Kumar Roy
The balance between mRNA synthesis and degradation plays an important role in gene regulation, their perturbation can lead to deleterious consequences to the cell. In eukaryotes, mRNA is degraded by a decapping protein-2 (DCP2). A hypomorph mutant allele of DCP2, DCP2l(3)tb, identified in our lab, shows delayed moulting, pupariation and absolute lethality in pupal stages. In Drosophila, moulting and pupariation are primarily regulated by ecdysone which is modulated by a few regulators synthesized by the larval brain, some are stimulatory such as Prothoracicotropic hormone (PTTH) and Drosophila insulin-like peptides (Dilps); whereas some are inhibitory, such as Lgr3-expressing neurons. We aimed to investigate the cause of the delay in moulting and pupariation in DCP2l(3)tb homozygous mutants. Through our RNA Seq data, we found downregulated expression of brain-derived neuropeptides such as PTTH and Dilps which were further confirmed and validated through qRT-PCR and semiquantitative PCR. Furthermore, we assessed the mRNA level of Lgr3 which was found to be upregulated in the larval CNS of DCP2l(3)tb homozygotes suggesting insufficient production of stimulatory modulators. Further, providing 20H-ecdysone exogenously through diet, curtailed the extended larval life. We propose that the larval CNS of DCP2l(3)tb homozygotes produces insufficient brain-derived neuropeptides to stimulate the prothoracic gland to synthesize the ecdysone required for moulting and metamorphosis.
mRNA合成和降解之间的平衡在基因调控中起着重要作用,它们的干扰可能导致对细胞有害的后果。在真核生物中,mRNA被脱帽蛋白-2 (DCP2)降解。在我们的实验室中发现了DCP2的一个低变形突变等位基因DCP2l(3)tb,该等位基因在蛹期表现出蜕皮和羽化延迟和绝对致命性。在果蝇中,蜕皮和化蛹主要受蜕皮激素的调控,蜕皮激素由幼虫大脑合成的少数调节因子调节,其中一些是刺激性的,如促胸激素(pth)和果蝇胰岛素样肽(Dilps);而有些是抑制性的,比如表达lgr3的神经元。我们的目的是研究纯合突变体dcp21(3)的蜕皮和羽化延迟的原因。通过RNA Seq数据,我们发现PTTH和Dilps等脑源性神经肽的表达下调,并通过qRT-PCR和半定量PCR进一步证实和验证。此外,我们评估了Lgr3的mRNA水平,发现Lgr3在dcp21(3)的幼虫中枢神经系统中通过纯合子上调,表明刺激调节剂的产生不足。此外,通过饮食外源性提供20h -蜕皮激素,减少了延长的幼虫寿命。我们认为,DCP2l(3)tb纯合子的幼虫中枢神经系统产生的脑源神经肽不足以刺激前胸腺合成蜕皮和变态所需的蜕皮素。
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引用次数: 0
Molecular mechanisms of cuproptosis in osteoarthritis: Pathways, crosstalk, and therapeutic opportunities 骨关节炎中铜骨畸形的分子机制:途径、串扰和治疗机会。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-20 DOI: 10.1016/j.yexcr.2025.114800
Yanyang Shen , Mingdong Liu , Benson O.A. Botchway , Yong Zhang , Xuehong Liu
Osteoarthritis (OA), the most prevalent degenerative joint disorder worldwide, continues to impose significant personal and societal burdens due to the absence of effective disease-modifying therapies. Recent advances in metallobiology have identified cuproptosis, a copper (Cu)-dependent regulated cell death pathway, as a potential driver of OA pathogenesis. In OA, dysregulated Cu homeostasis has been linked to oxidative stress, inflammatory signalling activation, mitochondrial dysfunction, and direct chondrocyte injury. Mechanistically, Cu2+ overload promotes aggregation of lipoylated tricarboxylic acid (TCA) cycle enzymes and destabilisation of iron–sulfur clusters, thereby impairing mitochondrial integrity and cellular metabolism. Emerging evidence also highlights extensive crosstalk between cuproptosis and ferroptosis, mediated largely by glutathione depletion and glutathione peroxidase 4 (GPX4) dysfunction, which amplifies oxidative damage in joint tissues. This review synthesises current evidence on Cu metabolism, the regulation and function of cuproptosis-related genes (CRGs), and their roles in immune infiltration, inflammatory signalling, and cartilage degeneration in OA. We further examine the interplay between cuproptosis and ferroptosis, and critically evaluate therapeutic strategies, including Cu chelation, antioxidant reinforcement, and pathway modulation, that may offer disease-modifying potential. By integrating these mechanistic insights, we aim to define new translational opportunities for OA management and outline priority areas for future research.
骨关节炎(OA)是世界上最常见的退行性关节疾病,由于缺乏有效的疾病改善治疗,它继续给个人和社会带来重大负担。金属生物学的最新进展已经确定了铜增生,一种依赖铜(Cu)调节的细胞死亡途径,是OA发病的潜在驱动因素。在骨性关节炎中,铜稳态失调与氧化应激、炎症信号激活、线粒体功能障碍和直接软骨细胞损伤有关。机制上,Cu2+超载促进脂酰化三羧酸(TCA)循环酶的聚集和铁硫簇的不稳定,从而损害线粒体的完整性和细胞代谢。新出现的证据也强调了铜下垂和铁下垂之间广泛的串扰,主要是由谷胱甘肽消耗和谷胱甘肽过氧化物酶4 (GPX4)功能障碍介导的,这加剧了关节组织的氧化损伤。本文综述了目前关于骨关节炎中铜代谢、铜中毒相关基因(CRGs)的调控和功能,以及它们在免疫浸润、炎症信号传导和软骨退行性变中的作用。我们进一步研究了铜下垂和铁下垂之间的相互作用,并批判性地评估了治疗策略,包括铜螯合、抗氧化强化和途径调节,这些可能提供疾病改善的潜力。通过整合这些机制的见解,我们的目标是为OA管理定义新的转化机会,并概述未来研究的优先领域。
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引用次数: 0
Corrigendum to ‘Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway’ [Exp Cell Res. 2018 Jan 15;362(2):362–369] “辛伐他汀通过增加PTEN-PI3K/AKT通路的放射敏感性和逆转EMT过程来抑制放射耐药食管癌细胞的发展”的更正[Exp Cell Res. 2018 1月15日;362(2):362-369]。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-16 DOI: 10.1016/j.yexcr.2025.114792
Yingying Jin, Kun Xu, Qingjuan Chen, Baofeng Wang, Jiyuan Pan, Shan Huang, Yang Wei, Hongbing Ma
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引用次数: 0
Maternal protein restriction promotes cardiac disorders by disrupting heart developmental morphophysiology in young male offspring rats 母体蛋白限制通过破坏年轻雄性后代大鼠心脏发育形态生理促进心脏疾病。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-15 DOI: 10.1016/j.yexcr.2025.114795
Lucas Sobrinho Lemos , Matheus Naia Fioretto , Isabelle Tenori Ribeiro , Luísa Annibal Barata , Flávia Alessandra Maciel , Felipe Leonardo Fagundes , Renato Mattos , Luiz Marcos Frediani Portela , João Miguel Barboza , Beatriz Souza de Oliveira , Keila Emílio de Almeida , Sérgio Alexandre Alcantara dos Santos , Clélia Akiko Hiruma Lima , José Ricardo de Arruda Miranda , Elena Zambrano , Luis Antonio Justulin
In recent years, cardiovascular diseases have been one of the leading causes of death worldwide. Epidemiological and experimental studies have linked adverse intrauterine conditions with an susceptibility to cardiovascular and metabolic diseases in subsequent generations, a concept related to the Developmental Origins of Health and Disease (DOHaD). Here, we evaluated the maternal protein restriction (MPR), and its harmful effects on the cardiac morphophysiology of offspring in early life. During gestation and lactation, the pregnant rats were divided into two groups: Control (CTR), which received a normoprotein diet (17 % protein), and Gestational and Lactational Low-Protein (GLLP), which received a hypoprotein diet (6 % protein). At postnatal day 21, the offspring were euthanized. There was a decrease in serum levels of IGF1, an increase in testosterone, and a decrease in several phenotypic parameters in the heart, such as the size of cardiomyocytes and their nuclei, collagen, reticular and elastic fibers, and mast cells in the GLLP group. We observed that MPR led to electrical disorders in the heart (bradycardia), in addition to impacting angiogenic proteins (high Aquaporin1 and PECAM-1), and proteins associated with the antioxidant system (low Peroxiredoxin 4 and high GSTpi expressions) in the GLLP group. These adverse effects early in life increase the risk of pathophysiological remodeling of the heart, with the potential for hypertension, hypertrophy, and cardiovascular disease later in life.
近年来,心血管疾病已成为世界范围内死亡的主要原因之一。流行病学和实验研究已将宫内不良状况与后代易患心血管和代谢性疾病联系起来,这一概念与健康和疾病的发育起源有关。在此,我们评估了母体蛋白限制(MPR)及其对后代早期心脏形态生理的有害影响。在妊娠和哺乳期,将妊娠大鼠分为两组:对照组(CTR)给予正常蛋白饮食(17%蛋白),妊娠和哺乳期低蛋白饮食(GLLP)给予低蛋白饮食(6%蛋白)。在出生后第21天,对后代实施安乐死。GLLP组血清IGF1水平降低,睾酮水平升高,心脏的一些表型参数减少,如心肌细胞及其细胞核的大小、胶原蛋白、网状纤维和弹性纤维以及肥大细胞。我们观察到,在GLLP组中,MPR除了影响血管生成蛋白(高水通道蛋白1和PECAM-1)和与抗氧化系统相关的蛋白(低过氧化氧还蛋白4和高GSTpi表达)外,还导致心脏电障碍(心动过缓)。生命早期的这些不良影响增加了心脏病理生理重塑的风险,并有可能在以后的生活中发生高血压、肥厚和心血管疾病。
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引用次数: 0
Bone marrow mesenchymal stem cell-derived exosomes HADH alleviate vitiligo by activating the Nrf2/HO-1 pathway 骨髓间充质干细胞来源的外泌体HADH通过激活Nrf2/HO-1途径缓解白癜风。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-15 DOI: 10.1016/j.yexcr.2025.114798
Shiyang Tang , Xin Li , Jianyuan Xi

Background

Vitiligo is a chronic skin disorder that significantly impairs patients' quality of life. Exosomes (Exos) have been reported to hold therapeutic promise for vitiligo. This study aimed to investigate the molecular mechanism by which bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) ameliorate vitiligo.

Methods

In vitro vitiligo cell model was established by hydrogen peroxide (H2O2)-induced melanocytes. A mouse model of vitiligo was also established. Immunofluorescence, cell counting kit-8, 2′,7′-dichlorofluorescein diacetate, enzyme linked immunosorbent assay, flow cytometry, real-time quantitative PCR, western blotting, hematoxylin-eosin, Masson-Fontana, and immunohistochemistry staining experiments were elucidated to explore the molecular mechanism of BMSC-Exos in relieving vitiligo.

Results

H2O2 treatment reduce the cell viability, superoxide dismutase and catalase activities, and promote reactive oxygen species production, pyroptosis, the expression of NLRP3, ASC, IL-1β and IL-18 proteins in melanocytes. BMSC-Exos treatment effectively counteracted these detrimental effects. Knockdown of exosomal HADH derived from BMSC enhanced H2O2-induced oxidative stress and pyroptosis in melanocytes. Mechanistically, BMSC-Exos attenuated H2O2-induced oxidative stress and pyroptosis by mediating HADH delivery to activate the Nrf2/HO-1 pathway. Moreover, these results were further confirmed by experiments in a mouse model of vitiligo.

Conclusion

BMSC-Exos can alleviate vitiligo by delivering HADH to activate the Nrf2/HO-1 pathway. This study provides insights for exploring new treatments for vitiligo.
背景:白癜风是一种慢性皮肤病,严重影响患者的生活质量。外泌体(Exos)已被报道为白癜风的治疗前景。本研究旨在探讨骨髓间充质干细胞衍生外泌体(BMSC-Exos)改善白癜风的分子机制。方法:采用过氧化氢(H2O2)诱导黑色素细胞建立体外白癜风细胞模型。建立了白癜风小鼠模型。通过免疫荧光、细胞计数试剂盒- 8,2′,7′-二氯荧光素双醋酸酯、酶联免疫吸附、流式细胞术、实时定量PCR、western blotting、苏木精-伊红、Masson-Fontana、免疫组织化学染色等实验,探讨BMSC-Exos缓解白癜风的分子机制。结果:H2O2处理降低了黑素细胞的细胞活力、超氧化物歧化酶和过氧化氢酶活性,促进了活性氧的产生和焦亡,促进了NLRP3、ASC、IL-1β和IL-18蛋白的表达。BMSC-Exos治疗有效地抵消了这些有害影响。BMSC来源的外泌体HADH的敲除增强了h2o2诱导的黑素细胞氧化应激和焦亡。在机制上,BMSC-Exos通过介导HADH传递激活Nrf2/HO-1途径来减弱h2o2诱导的氧化应激和焦亡。此外,这些结果在白癜风小鼠模型的实验中得到进一步证实。结论:BMSC-Exos可通过传递HADH激活Nrf2/HO-1通路缓解白癜风。本研究为探索白癜风的新治疗方法提供了见解。
{"title":"Bone marrow mesenchymal stem cell-derived exosomes HADH alleviate vitiligo by activating the Nrf2/HO-1 pathway","authors":"Shiyang Tang ,&nbsp;Xin Li ,&nbsp;Jianyuan Xi","doi":"10.1016/j.yexcr.2025.114798","DOIUrl":"10.1016/j.yexcr.2025.114798","url":null,"abstract":"<div><h3>Background</h3><div>Vitiligo is a chronic skin disorder that significantly impairs patients' quality of life. Exosomes (Exos) have been reported to hold therapeutic promise for vitiligo. This study aimed to investigate the molecular mechanism by which bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) ameliorate vitiligo.</div></div><div><h3>Methods</h3><div><em>In vitro</em> vitiligo cell model was established by hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced melanocytes. A mouse model of vitiligo was also established. Immunofluorescence, cell counting kit-8, 2′,7′-dichlorofluorescein diacetate, enzyme linked immunosorbent assay, flow cytometry, real-time quantitative PCR, western blotting, hematoxylin-eosin, Masson-Fontana, and immunohistochemistry staining experiments were elucidated to explore the molecular mechanism of BMSC-Exos in relieving vitiligo.</div></div><div><h3>Results</h3><div>H<sub>2</sub>O<sub>2</sub> treatment reduce the cell viability, superoxide dismutase and catalase activities, and promote reactive oxygen species production, pyroptosis, the expression of NLRP3, ASC, IL-1β and IL-18 proteins in melanocytes. BMSC-Exos treatment effectively counteracted these detrimental effects. Knockdown of exosomal HADH derived from BMSC enhanced H<sub>2</sub>O<sub>2</sub>-induced oxidative stress and pyroptosis in melanocytes. Mechanistically, BMSC-Exos attenuated H<sub>2</sub>O<sub>2</sub>-induced oxidative stress and pyroptosis by mediating HADH delivery to activate the Nrf2/HO-1 pathway. Moreover, these results were further confirmed by experiments in a mouse model of vitiligo.</div></div><div><h3>Conclusion</h3><div>BMSC-Exos can alleviate vitiligo by delivering HADH to activate the Nrf2/HO-1 pathway. This study provides insights for exploring new treatments for vitiligo.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 2","pages":"Article 114798"},"PeriodicalIF":3.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Integrative multi-omics analysis identifies mitochondria- and ferroptosis-related prognostic genes in cervical cancer 综合多组学分析确定了宫颈癌中线粒体和铁凋亡相关的预后基因。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-15 DOI: 10.1016/j.yexcr.2025.114796
Linlin Jia , Xinyu Cui , Xiaoting Li , Rui Li

Background

Mitochondria and ferroptosis are crucial in tumorigenesis. However, their specific role in cervical cancer (CC) remains unclear. This study aimed to identify and validate prognostic genes linked to mitochondrial function and ferroptosis in CC.

Methods

Publicly available datasets were analyzed, including 306 CC tumor samples from The Cancer Genome Atlas-Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC), with survival data for 293 samples, a training set of 24 normal and 33 tumor tissues (GSE9750), and a validation set of 300 tumor tissues (GSE44001). Prognostic genes associated with mitochondria-related genes (MRGs) and ferroptosis-related genes (FRGs) were identified through machine learning, univariate Cox regression, Weighted Gene Co-expression Network Analysis (WGCNA), Mendelian randomization (MR), differential expression analysis, and multivariate Cox analysis. A risk model was constructed and validated, with the High-Risk Group (HRG) and Low-Risk Group (LRG) defined by optimal risk score thresholds. Independent prognostic analysis, functional enrichment, immune infiltration profiling, and single-cell resolution studies were conducted to explore the underlying molecular mechanisms. Additionally, gene expression was validated in five paired clinical samples (5 tumor/5 normal tissues) using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

Results

HSDL2, AMACR, and CBR3 were identified as prognostic genes. The risk model indicated significantly poorer survival rates in HRG patients (P < 0.05). It demonstrated strong predictive performance, with area under the curve (AUC) values exceeding 0.7 in both the training and validation sets. The risk score, tumor (T) stage, and lymph node (N) stage were identified as independent prognostic factors for a nomogram model (hazard ratio (HR ≠ 1, P < 0.5). Pathways co-enriched by these markers, such as allograft rejection, were investigated. Immune infiltration analysis revealed significant differences between HRG and LRG in M0 macrophages and resting myeloid dendritic cells (mDCs) (P < 0.5). Macrophages and epithelial/cancer cells were identified as key contributors to CC progression, exhibiting 13 and 7 distinct differentiation states, respectively, in pseudo-time analysis. Notably, HSDL2 and CBR3 expression levels were significantly different between normal and CC samples (P < 0.05).

Conclusion

HSDL2, AMACR, and CBR3 were established as prognostic biomarkers for CC. The risk model demonstrated robust predictive accuracy, offering a scientific foundation for clinical prognosis prediction in CC.
背景:线粒体和铁下垂在肿瘤发生中起关键作用。然而,它们在宫颈癌(CC)中的具体作用尚不清楚。方法:对来自Cancer Genome - cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC)的306例CC肿瘤样本、293例样本的生存数据、24例正常组织(GSE9750)和33例肿瘤组织(GSE44001)的训练组和300例肿瘤组织的验证组进行分析。通过机器学习、单因素Cox回归、加权基因共表达网络分析(WGCNA)、孟德尔随机化(MR)、差异表达分析和多因素Cox分析,鉴定与线粒体相关基因(MRGs)和凋亡相关基因(FRGs)相关的预后基因。构建风险模型并进行验证,以最优风险评分阈值定义高风险组(HRG)和低风险组(LRG)。通过独立的预后分析、功能富集、免疫浸润谱和单细胞分辨率研究来探索潜在的分子机制。此外,利用逆转录-定量聚合酶链反应(RT-qPCR)在5个配对的临床样本(5个肿瘤/5个正常组织)中验证基因表达。结果:HSDL2、AMACR和CBR3被确定为预后基因。风险模型显示HRG患者生存率明显较低(P < 0.05)。它表现出很强的预测性能,在训练集和验证集中,曲线下面积(AUC)值都超过0.7。风险评分、肿瘤(T)分期和淋巴结(N)分期被确定为nomogram模型的独立预后因素(风险比(HR≠1,P < 0.5)。研究了这些标记共同富集的途径,如同种异体移植排斥反应。免疫浸润分析显示,M0巨噬细胞和静息髓样树突状细胞(mDCs) HRG和LRG差异有统计学意义(P < 0.5)。在伪时间分析中,巨噬细胞和上皮/癌细胞被确定为CC进展的关键贡献者,分别表现出13种和7种不同的分化状态。值得注意的是,HSDL2和CBR3的表达水平在正常和CC样本中有显著差异(P < 0.05)。结论:HSDL2、AMACR、CBR3可作为CC的预后生物标志物,该风险模型具有较强的预测准确性,为CC的临床预后预测提供了科学依据。
{"title":"Integrative multi-omics analysis identifies mitochondria- and ferroptosis-related prognostic genes in cervical cancer","authors":"Linlin Jia ,&nbsp;Xinyu Cui ,&nbsp;Xiaoting Li ,&nbsp;Rui Li","doi":"10.1016/j.yexcr.2025.114796","DOIUrl":"10.1016/j.yexcr.2025.114796","url":null,"abstract":"<div><h3>Background</h3><div>Mitochondria and ferroptosis are crucial in tumorigenesis. However, their specific role in cervical cancer (CC) remains unclear. This study aimed to identify and validate prognostic genes linked to mitochondrial function and ferroptosis in CC.</div></div><div><h3>Methods</h3><div>Publicly available datasets were analyzed, including 306 CC tumor samples from The Cancer Genome Atlas-Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC), with survival data for 293 samples, a training set of 24 normal and 33 tumor tissues (GSE9750), and a validation set of 300 tumor tissues (GSE44001). Prognostic genes associated with mitochondria-related genes (MRGs) and ferroptosis-related genes (FRGs) were identified through machine learning, univariate Cox regression, Weighted Gene Co-expression Network Analysis (WGCNA), Mendelian randomization (MR), differential expression analysis, and multivariate Cox analysis. A risk model was constructed and validated, with the High-Risk Group (HRG) and Low-Risk Group (LRG) defined by optimal risk score thresholds. Independent prognostic analysis, functional enrichment, immune infiltration profiling, and single-cell resolution studies were conducted to explore the underlying molecular mechanisms. Additionally, gene expression was validated in five paired clinical samples (5 tumor/5 normal tissues) using reverse transcription-quantitative polymerase chain reaction (RT-qPCR).</div></div><div><h3>Results</h3><div>HSDL2, AMACR, and CBR3 were identified as prognostic genes. The risk model indicated significantly poorer survival rates in HRG patients (P &lt; 0.05). It demonstrated strong predictive performance, with area under the curve (AUC) values exceeding 0.7 in both the training and validation sets. The risk score, tumor (T) stage, and lymph node (N) stage were identified as independent prognostic factors for a nomogram model (hazard ratio (HR ≠ 1, P &lt; 0.5). Pathways co-enriched by these markers, such as allograft rejection, were investigated. Immune infiltration analysis revealed significant differences between HRG and LRG in M0 macrophages and resting myeloid dendritic cells (mDCs) (P &lt; 0.5). Macrophages and epithelial/cancer cells were identified as key contributors to CC progression, exhibiting 13 and 7 distinct differentiation states, respectively, in pseudo-time analysis. Notably, HSDL2 and CBR3 expression levels were significantly different between normal and CC samples (P &lt; 0.05).</div></div><div><h3>Conclusion</h3><div>HSDL2, AMACR, and CBR3 were established as prognostic biomarkers for CC. The risk model demonstrated robust predictive accuracy, offering a scientific foundation for clinical prognosis prediction in CC.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 2","pages":"Article 114796"},"PeriodicalIF":3.5,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145312756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
RNF216P1 functions as an oncogenic gene through modulating miR-195-5p/ATG4B axis in hepatocellular carcinoma RNF216P1在肝细胞癌中通过调控miR-195-5p/ATG4B轴发挥致癌基因的作用。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-14 DOI: 10.1016/j.yexcr.2025.114797
Kai Li , Yaping Bai , Jingtong Wang , Li Ren , Anqi Mo , Haijun Liu , Wenjun Pei
Recent studies have highlighted the critical roles of long non-coding RNAs (lncRNAs) in tumorigenesis and progression. Here, we report that the lncRNA RNF216P1 is significantly upregulated in hepatocellular carcinoma (HCC) and contributes to tumor growth. To elucidate its underlying mechanisms, we first analyzed the transcriptional levels of RNF216P1 and its targets, miR-195-5p and autophagy related 4B cysteine peptidase (ATG4B), in HCC tissues using The Cancer Genome Atlas dataset, followed by validation with RT-qPCR. ATG4B protein levels were assessed by Western blotting. Functional assays—including xenograft models, CCK-8 viability tests, wound-healing assays, and Transwell migration assays—were performed to evaluate the role of RNF216P1 in HCC progression. Furthermore, the interactions between RNF216P1 and miR-195-5p, as well as between miR-195-5p and ATG4B, were confirmed by fluorescence in situ hybridization (FISH), RNA immunoprecipitation assays, and dual-luciferase reporter assays. Collectively, our findings demonstrate that RNF216P1 promotes malignant progression in HCC cells by acting as a competing endogenous RNA for miR-195-5p, thereby upregulating ATG4B and enhancing autophagy. This study identifies a novel ceRNA axis—RNF216P1/miR-195-5p/ATG4B—that plays a pivotal role in HCC development and may represent a potential therapeutic target.
最近的研究强调了长链非编码rna (lncRNAs)在肿瘤发生和发展中的关键作用。在这里,我们报道了lncRNA RNF216P1在肝细胞癌(HCC)中显著上调并促进肿瘤生长。为了阐明其潜在的机制,我们首先使用Cancer Genome Atlas数据集分析了HCC组织中RNF216P1及其靶点miR-195-5p和自噬相关的4B半胱氨酸肽酶(ATG4B)的转录水平,然后使用RT-qPCR进行验证。Western blotting检测ATG4B蛋白水平。功能分析包括异种移植模型、CCK-8活力测试、伤口愈合测试和Transwell迁移测试,以评估RNF216P1在HCC进展中的作用。此外,RNF216P1与miR-195-5p之间以及miR-195-5p与ATG4B之间的相互作用通过荧光原位杂交(FISH)、RNA免疫沉淀测定和双荧光素酶报告基因测定证实。总的来说,我们的研究结果表明,RNF216P1通过作为miR-195-5p的竞争内源性RNA促进HCC细胞的恶性进展,从而上调ATG4B并增强自噬。本研究确定了一种新的ceRNA轴- rnf216p1 /miR-195-5p/ atg4b -在HCC发展中起关键作用,可能代表潜在的治疗靶点。
{"title":"RNF216P1 functions as an oncogenic gene through modulating miR-195-5p/ATG4B axis in hepatocellular carcinoma","authors":"Kai Li ,&nbsp;Yaping Bai ,&nbsp;Jingtong Wang ,&nbsp;Li Ren ,&nbsp;Anqi Mo ,&nbsp;Haijun Liu ,&nbsp;Wenjun Pei","doi":"10.1016/j.yexcr.2025.114797","DOIUrl":"10.1016/j.yexcr.2025.114797","url":null,"abstract":"<div><div>Recent studies have highlighted the critical roles of long non-coding RNAs (lncRNAs) in tumorigenesis and progression. Here, we report that the lncRNA RNF216P1 is significantly upregulated in hepatocellular carcinoma (HCC) and contributes to tumor growth. To elucidate its underlying mechanisms, we first analyzed the transcriptional levels of RNF216P1 and its targets, miR-195-5p and autophagy related 4B cysteine peptidase (ATG4B), in HCC tissues using The Cancer Genome Atlas dataset, followed by validation with RT-qPCR. ATG4B protein levels were assessed by Western blotting. Functional assays—including xenograft models, CCK-8 viability tests, wound-healing assays, and Transwell migration assays—were performed to evaluate the role of RNF216P1 in HCC progression. Furthermore, the interactions between RNF216P1 and miR-195-5p, as well as between miR-195-5p and ATG4B, were confirmed by fluorescence in situ hybridization (FISH), RNA immunoprecipitation assays, and dual-luciferase reporter assays. Collectively, our findings demonstrate that RNF216P1 promotes malignant progression in HCC cells by acting as a competing endogenous RNA for miR-195-5p, thereby upregulating ATG4B and enhancing autophagy. This study identifies a novel ceRNA axis—RNF216P1/miR-195-5p/ATG4B—that plays a pivotal role in HCC development and may represent a potential therapeutic target.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"453 1","pages":"Article 114797"},"PeriodicalIF":3.5,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145307250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
FERMT1 suppresses the ferroptosis of glioma cells by interacting with MBOAT2 FERMT1通过与MBOAT2相互作用抑制胶质瘤细胞的铁下垂。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-13 DOI: 10.1016/j.yexcr.2025.114794
Zhigang Pan , Chuhan Ke , Bojun Zhang , Qingxin Lin , Hanlin Zheng , Shuni Zheng , Jinzhong Huang , Weipeng Hu
Gliomas, particularly high-grade glioblastomas, are highly aggressive malignancies with limited treatment options and poor prognosis. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target in cancer. However, the mechanisms regulating ferroptosis in glioma remain poorly understood. In this study, we identify FERMT1 as a key suppressor of ferroptosis in glioma cells. Using gain and loss-of-function experiments, we demonstrate that FERMT1 overexpression protects glioma cells from erastin-induced ferroptosis, while FERMT1 deficiency sensitizes cells to ferroptotic cell death. Treatment with the ferroptosis inhibitor ferrostatin-1 mitigates the effects of FERMT1 deficiency, underscoring the importance of ferroptosis suppression in FERMT1-mediated oncogenesis. Mechanistically, FERMT1 interacts with MBOAT2 to suppress ferroptosis. Depletion of MBOAT2 abolishes the anti-ferroptotic effects of FERMT1, whereas MBOAT2 overexpression rescues ferroptosis in FERMT1-deficient cells. Collectively, our findings reveal a previously unrecognized FERMT1-MBOAT2 axis that regulates ferroptosis in glioma cells and provide new insights into the molecular mechanisms underlying glioma progression. Targeting this axis may offer a novel therapeutic strategy for inducing ferroptosis and improving treatment outcomes in glioma.
胶质瘤,特别是高级别胶质母细胞瘤,是一种高度侵袭性的恶性肿瘤,治疗选择有限,预后差。铁下垂是一种由脂质过氧化驱动的铁依赖性细胞死亡形式,已成为癌症治疗中有希望的治疗靶点。然而,调控胶质瘤中铁下垂的机制仍然知之甚少。在这项研究中,我们发现FERMT1是神经胶质瘤细胞铁下垂的关键抑制因子。通过功能增益和功能丧失实验,我们证明FERMT1过表达可以保护胶质瘤细胞免受橡皮蛋白诱导的铁凋亡,而FERMT1缺乏则会使细胞对铁凋亡细胞死亡敏感。使用铁下垂抑制剂铁抑素-1治疗可减轻FERMT1缺乏的影响,强调抑制铁下垂在FERMT1介导的肿瘤发生中的重要性。机制上,FERMT1与MBOAT2相互作用抑制铁下垂。MBOAT2的缺失可消除FERMT1的抗铁凋亡作用,而MBOAT2过表达可恢复FERMT1缺陷细胞中的铁凋亡。总的来说,我们的研究结果揭示了一个以前未被识别的FERMT1-MBOAT2轴,它调节胶质瘤细胞中的铁凋亡,并为胶质瘤进展的分子机制提供了新的见解。以该轴为靶点可能为神经胶质瘤诱导铁下垂和改善治疗效果提供一种新的治疗策略。
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引用次数: 0
Intraindividual rDNA copy number variation and methylation in humans 人类个体内rDNA拷贝数变异和甲基化。
IF 3.5 3区 生物学 Q3 CELL BIOLOGY Pub Date : 2025-10-13 DOI: 10.1016/j.yexcr.2025.114793
Jana Durackova , Ramya Potabattula , Andreas Rosenwald , Thomas Haaf
The absolute number of rDNA transcription units (TU) can vary by about one order of ten among individuals. Apart from extensive rDNA copy number (CN) variation and instability in many cancers, there is little information on the extent of intraindividual CN variation between normal tissues. Here we used droplet digital PCR and deep bisulfite sequencing to determine both the absolute rDNA CN and the number of presumably active CN with a hypomethylated (≤10 %) promoter region in up to six different tissues of 13 autopsy probands. In general, the absolute rDNA CN as well as the frequency of the minor A variant were highly similar between tissues (cerebellum, cerebrum, colon, heart, intestine, kidney, liver, and spleen) of the same individual. However, in some probands absolute CN in one or multiple tissues was much higher than in the other tissues, indicative of relaxation/breakdown of the CN control system. The amplified copies were inactivated by promoter methylation and, thus, the number of active CN was largely independent from absolute CN. Collectively, our data suggest that with some notable exceptions absolute and even more active rDNA CN are maintained during development and differentiation in different tissues of the same individual. Despite the low intraindividual variation active CN appeared to systematically vary between tissues. Cerebellum and cerebrum consistently exhibited lower active CN than the other analyzed tissues. We estimate that >50 active rDNA TU are required for normal tissue/organ function.
rDNA转录单位(TU)的绝对数量在个体之间可以变化大约10个数量级。除了在许多癌症中广泛存在的rDNA拷贝数(CN)变异和不稳定性外,关于正常组织之间个体内CN变异程度的信息很少。在这里,我们使用液滴数字PCR和深度亚硫酸盐测序来确定13个尸检先证的6个不同组织中rDNA CN的绝对数量和可能具有低甲基化(≤10%)启动子区域的活性CN的数量。一般来说,同一个体的组织(小脑、大脑、结肠、心、肠、肾、肝、脾)的绝对rDNA CN和小变异A的频率高度相似。然而,在一些先证中,一个或多个组织的绝对CN远高于其他组织,表明CN控制系统松弛/崩溃。扩增的拷贝被启动子甲基化灭活,因此,活性CN的数量在很大程度上与绝对CN无关。总的来说,我们的数据表明,除了一些明显的例外,在同一个体的不同组织的发育和分化过程中,绝对的甚至更活跃的rDNA CN是保持不变的。尽管个体内变异较低,但活性CN似乎在组织间有系统地变化。小脑和大脑的CN活性始终低于其他分析组织。我们估计正常的组织/器官功能需要50个活性rDNA TU。
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Experimental cell research
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