Biochimica et biophysica acta. Molecular cell research最新文献_第9页

Insights into early cochlear damage induced by potassium channel deficiency 钾通道缺乏致早期耳蜗损伤的研究进展。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-08-05 DOI: 10.1016/j.bbamcr.2025.120030

Ezequiel Rías , Camila Carignano , Valeria C. Castagna , Leonardo Dionisio , Jimena A. Ballestero , Giuliana Paolillo , Ingrid Ouwerkerk , María Eugenia Gomez-Casati , Guillermo Spitzmaul

Hearing loss (HL) is the most common sensory disorder, caused by genetic mutations and acquired factors like presbycusis and noise exposure. A critical factor in HL development is the dysfunction of potassium (K⁺) channels, essential for sensory cell function in the organ of Corti (OC). Inner and outer hair cells (IHCs and OHCs) convert sound into electrical signals, while supporting cells (SCs) maintain ionic and structural balance. KCNQ4 channels, located in the basal membrane of OHCs, regulate K⁺ efflux. Mutations in KCNQ4 are linked to progressive HL (DFNA2), noise-induced hearing loss, and presbycusis, leading to K⁺ accumulation, cellular stress, and OHC death. Gene editing or pharmacological activation of KCNQ4 has shown potential in partially preventing HL in mouse models. In this study, we demonstrate KCNQ4 deletion disrupts the localization of key proteins like prestin and BK channels, alters OHC organization, and induces apoptosis in sensory and SC. Spiral ganglion neurons (SGNs) also degenerate over time. Despite these structural changes, noise exposure does not exacerbate OHC damage in our KCNQ4-deficient model. This highlights KCNQ4's role in maintaining ion homeostasis and cochlear function, as its absence triggers widespread dysfunction in the OC. The present study demonstrates that disruptions in a single cell type can have a cascade effect on overall cochlear health. Understanding the molecular and cellular consequences of KCNQ4 mutations is crucial for developing targeted therapies to mitigate progressive HL caused by genetic and environmental factors.

听力损失（HL）是最常见的感觉障碍，由基因突变和获得性因素如老年性耳聋和噪音暴露引起。HL发展的一个关键因素是钾（K+）通道的功能障碍，这对Corti器官（OC）的感觉细胞功能至关重要。内外部毛细胞（IHCs和OHCs）将声音转化为电信号，而支持细胞（SCs）维持离子和结构平衡。KCNQ4通道位于OHCs基膜，调节K+外排。KCNQ4突变与进行性HL （DFNA2）、噪声性听力损失和老年性耳聋有关，导致K+积累、细胞应激和OHC死亡。在小鼠模型中，基因编辑或药理激活KCNQ4已显示出部分预防HL的潜力。在这项研究中，我们证明KCNQ4缺失会破坏prestin和BK通道等关键蛋白的定位，改变OHC组织，诱导感觉和SC的凋亡。螺旋神经节神经元（sgn）也会随着时间的推移而退化。尽管存在这些结构变化，但在kcnq4缺陷模型中，噪声暴露不会加剧OHC损伤。这突出了KCNQ4在维持离子稳态和耳蜗功能中的作用，因为它的缺失会引发耳蜗OC中广泛的功能障碍。目前的研究表明，单个细胞类型的破坏可以对整个耳蜗健康产生级联效应。了解KCNQ4突变的分子和细胞后果对于开发靶向治疗以减轻由遗传和环境因素引起的进行性HL至关重要。

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引用次数: 0

SYK overexpression enhances microtubule instability in an MDA-MB-231-derived paclitaxel-resistant cell line 在mda - mb -231衍生的紫杉醇耐药细胞系中，SYK过表达增强微管不稳定性。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-09-08 DOI: 10.1016/j.bbamcr.2025.120059

Hsiao-Hui Kuo, Chien-Wei Huang, Wei-Rou Chiang, Chieh-Ting Fang, Shang-Yuan Liu, Ling-Huei Yih

Paclitaxel resistance is a major obstacle to achieving long-term remission in patients with triple-negative breast cancer (TNBC), and effective strategies to overcome drug resistance would have significant clinical impact. In this study, we established a paclitaxel-resistant cell clone, T50R, from the human TNBC cell line MDA-MD-231. Intriguingly, these drug-resistant T50R cells required paclitaxel for proliferation. When cultured in the absence of drug, the cells exhibited high dynamic instability of microtubules (MTs) and spindle abnormalities, causing their accumulation in mitosis phase and cell death. Thus, the increased instability of MTs in T50R cells may contribute to the drug requirement for cell growth and drug-resistant phenotype, as paclitaxel counteracts the effect. Compared to the parental MDA-MD-231 cells, T50R cells had elevated expression of spleen tyrosine kinase (SYK), and inhibition or depletion of SYK in the T50R cells cultured without paclitaxel restored MT stability, reduced spindle defects and rescued cell death, suggesting that SYK overexpression contributes to the enhanced MT instability in T50R cells. Furthermore, T50R cells exhibited signs of ER stress and underwent ferroptotic cell death when cultured without paclitaxel, both of which could be ameliorated by inhibition of SYK. Finally, small molecules that target SYK or induce ferroptosis could significantly enhance T50R cell sensitivity to paclitaxel. Together, our results show that SYK-enhanced MT dynamic instability can play an important role in paclitaxel resistance and that targeting the SYK pathway may enhance paclitaxel response.

紫杉醇耐药是三阴性乳腺癌（TNBC）患者实现长期缓解的主要障碍，克服耐药的有效策略将具有重大的临床影响。在这项研究中，我们从人TNBC细胞系MDA-MD-231中建立了紫杉醇耐药细胞克隆T50R。有趣的是，这些耐药T50R细胞需要紫杉醇才能增殖。在没有药物的情况下，细胞表现出微管（mt）的高度动态不稳定性和纺锤体异常，导致它们在有丝分裂期积聚和细胞死亡。因此，T50R细胞中MTs不稳定性的增加可能有助于细胞生长和耐药表型的药物需求，因为紫杉醇抵消了这种作用。与亲代MDA-MD-231细胞相比，T50R细胞中脾脏酪氨酸激酶（SYK）的表达升高，不含紫杉醇培养的T50R细胞中SYK的抑制或缺失恢复了MT的稳定性，减少了纺锤体缺陷，挽救了细胞死亡，表明SYK的过表达导致了T50R细胞MT的不稳定性增强。此外，在不添加紫杉醇的情况下，T50R细胞表现出内质网应激的迹象，并发生铁致细胞死亡，这两种情况都可以通过抑制SYK来改善。最后，靶向SYK或诱导铁下垂的小分子可显著增强T50R细胞对紫杉醇的敏感性。综上所述，我们的研究结果表明SYK增强的MT动态不稳定性在紫杉醇耐药中起重要作用，靶向SYK通路可能增强紫杉醇应答。

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引用次数: 0

Intracellular calcium-induced ROS generation promotes squaraine phototoxicity 细胞内钙诱导的ROS生成促进方碱光毒性。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-08-30 DOI: 10.1016/j.bbamcr.2025.120055

Giorgia Chinigò , Carlotta Pontremoli , Francesca Bianco , Alessandra Gilardino , Maria Jesus Moran Plata , Alessia Brossa , Benedetta Bussolati , Sonja Visentin , Nadia Barbero , Alessandra Fiorio Pla

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality approved by the Food and Drug Administration (FDA) for the treatment of several pathological conditions, including cancer. Developing new photosensitizers (PSs) for PDT is of great interest to increase the treatment efficacy while minimizing side effects. In this regard, a better understanding of the signal transduction triggered by PS photo-activation may help to optimize PS efficacy.

In the present work, we synthesized a series of squaraines (SQs) featuring different indolenine ring modifications. Our results show that unsubstituted SQ has significant phototoxic activity, further increased by the introduction of a bromine in the indolenine ring (Br-SQ-C4) as well as the replacement of the squaryl oxygen atoms with sulfur atoms (SQ-S-C4). Phototoxicity positively correlates with higher photo-induced cytoplasmic Ca²⁺ signals as well as reactive oxygen species (ROS) generation. However, the different substituents strongly affect the signaling pathway triggered. The bromine substituent strengthens the localization of the dye in the endoplasmic reticulum (ER), while the sulfur substituent shifts its preferential localization to the mitochondria. Consistently, photo-activation of Br-SQ-C4 induces a larger ER Ca²⁺ release followed by SOCE, which fuels secondary ROS generation able to sustain a remarkable mitochondrial Ca²⁺ uptake and subsequent mitochondrial ROS generation. On the other hand, SQ-S-C4 can induce, already at the basal level, a greater perturbation of the Ca²⁺/ROS dynamics.

Overall, our results contribute to a deeper understanding of the intracellular signaling triggered by SQs, paving the way for the development of novel strategies aimed at increasing PDT efficacy.

光动力疗法（PDT）是美国食品和药物管理局（FDA）批准的一种微创治疗方式，用于治疗包括癌症在内的几种病理状况。开发新型光敏剂是提高PDT治疗效果、减少副作用的重要途径。因此，更好地了解PS光激活引发的信号转导可能有助于优化PS的功效。在本工作中，我们合成了一系列具有不同吲哚胺环修饰的方胺类化合物。我们的研究结果表明，未取代的SQ具有显著的光毒性活性，并通过在吲哚环中引入一个溴（Br-SQ-C4）以及用硫原子取代方基氧原子（SQ- s - c4）进一步增强。光毒性与较高的光诱导细胞质Ca2+信号以及活性氧（ROS）的产生呈正相关。然而，不同的取代基强烈影响信号通路的触发。溴取代基加强了染料在内质网（ER）中的定位，而硫取代基将其优先定位转移到线粒体。一致地，Br-SQ-C4的光激活诱导更大的ER Ca2+释放，随后是SOCE，这促进了能够维持显着的线粒体Ca2+摄取和随后的线粒体ROS生成的二次ROS生成。另一方面，SQ-S-C4可以在基础水平上诱导Ca2+/ROS动力学的更大扰动。总的来说，我们的研究结果有助于更深入地了解SQs引发的细胞内信号传导，为开发旨在提高PDT疗效的新策略铺平道路。

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引用次数: 0

E3 ligase SMURF2 alleviated intrauterine adhesion by stabilizing SMAD6 E3连接酶SMURF2通过稳定SMAD6减轻宫内粘连。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-08-16 DOI: 10.1016/j.bbamcr.2025.120045

Ke Zhou , Yun Chen , Lishi Chen , Zhenfu Wu , Lirong Zhang , Jingjing Zheng , Song Tian , Mingzhu Wen , Xin Li , Huihua Cai

Intrauterine adhesion (IUA) is a debilitating uterine disorder characterized by endometrial fibrosis and infertility, for which effective treatments remain limited. Here, we identify the E3 ubiquitin ligase SMURF2 as a critical protective factor against IUA progression. SMURF2 expression was significantly upregulated in endometrial tissues of IUA patients, a murine IUA model, and TGF-β1-treated human endometrial stromal cells (HESCs). Functional analyses revealed that SMURF2 overexpression mitigated fibrosis-associated phenotypes, including enhanced cell proliferation, migration, and extracellular matrix accumulation, both in vitro and in vivo, whereas SMURF2 knockdown had the opposite effect. Mechanistically, SMURF2 directly interacted with the inhibitory SMAD protein SMAD6 and promoted its stabilization via K63-linked polyubiquitination. Mutation analysis confirmed that disruption of the K63 linkage markedly reduced SMAD6 ubiquitination and destabilized the protein. As a result, SMAD6 accumulation suppressed TGF-β/Smad signaling and downstream fibrotic gene expression. These findings reveal a previously unrecognized SMURF2–SMAD6 axis that counteracts endometrial fibrosis, and suggest that enhancing SMURF2-mediated K63-linked ubiquitination may offer a novel therapeutic avenue for IUA treatment.

宫内粘连（IUA）是一种以子宫内膜纤维化和不孕症为特征的衰弱性子宫疾病，有效的治疗方法仍然有限。在这里，我们发现E3泛素连接酶SMURF2是防止IUA进展的关键保护因子。SMURF2在IUA患者、小鼠IUA模型和TGF-β1处理的人子宫内膜基质细胞（HESCs）的子宫内膜组织中表达显著上调。功能分析显示，SMURF2过表达减轻了纤维化相关表型，包括体外和体内增强的细胞增殖、迁移和细胞外基质积累，而SMURF2敲低则具有相反的效果。在机制上，SMURF2直接与抑制SMAD蛋白SMAD6相互作用，并通过K63-linked多泛素化促进其稳定。突变分析证实，K63连锁的破坏显著降低了SMAD6的泛素化并使该蛋白不稳定。因此，SMAD6的积累抑制了TGF-β/Smad信号传导和下游纤维化基因的表达。这些发现揭示了以前未被识别的SMURF2-SMAD6轴可以抵消子宫内膜纤维化，并表明增强smurf2介导的k63连接泛素化可能为IUA治疗提供新的治疗途径。

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引用次数: 0

Loss of Prominin 2 expression inhibits AKT/mTOR signaling to limit glycolysis and drive ferroptosis in breast cancer cells 在乳腺癌细胞中，pronin2表达缺失可抑制AKT/mTOR信号通路限制糖酵解并驱动铁下垂。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-08-14 DOI: 10.1016/j.bbamcr.2025.120047

Lei Yin , Yanze Lin , Zhongdian Yuan , Rexiati Ruze , Zhen Yang , Yingmei Shao

This study aimed to characterize the oncogenic functions of Prominin 2 (PROM2), the pro-cancer and ferroptosis resistance gene, in breast cancer (BC). PROM2 expression was analyzed using single-cell RNA sequencing and the TCGA database. Its expression was confirmed in BC tissues and cell lines using qRT-PCR, immunohistochemistry, and western blot assays. The effects of PROM2 were evaluated in vivo and in vitro. RNA sequencing and GSEA were used to investigate the potential underlying molecular mechanisms of PROM2 in BC. Co-immunoprecipitation was used to determine the interaction between AKT and PROM2. PROM2 expression was elevated in clinical samples and BC cells and positively correlated with a worse prognosis. Functional experiments demonstrated that PROM2 silencing suppressed tumor growth and malignancy. Mechanistically, PROM2 interacts with AKT to activate mTOR signaling, thereby promoting glycolysis and inhibiting ferroptosis. Specifically, for glycolysis, PROM2 silencing decreased glucose uptake, extracellular acidification rate, lactate production, and glycolysis-related enzyme expression, while increasing oxygen consumption. For ferroptosis, PROM2 silencing upregulated reactive oxygen species, malondialdehyde, iron, Fe²⁺, and downregulated SLC7A11, GPX4, and glutathione levels. Overexpression of AKT or the AKT agonist (SC79) reversed the effects of PROM2 silencing on BC cell glycolysis and ferroptosis. Our results suggest that PROM2 is an oncogenic gene that supports BC progression by enhancing glycolysis and inhibiting ferroptosis via AKT/mTOR signaling. Therefore, PROM2 may be a potential therapeutic target for BC treatment.

本研究旨在探讨promein 2 （PROM2）在乳腺癌（BC）中的促癌和抗铁下垂基因的致癌功能。利用单细胞RNA测序和TCGA数据库分析PROM2的表达。通过qRT-PCR、免疫组织化学和western blot检测证实其在BC组织和细胞系中的表达。在体内和体外评价PROM2的作用。利用RNA测序和GSEA研究了PROM2在BC中的潜在分子机制。共免疫沉淀法测定AKT与PROM2的相互作用。PROM2在临床样本和BC细胞中的表达升高，并与较差的预后呈正相关。功能实验表明，PROM2沉默抑制肿瘤生长和恶性。机制上，PROM2与AKT相互作用激活mTOR信号，从而促进糖酵解，抑制铁下垂。具体来说，对于糖酵解，PROM2沉默降低了葡萄糖摄取、细胞外酸化速率、乳酸生成和糖酵解相关酶的表达，同时增加了氧气消耗。对于铁死亡，PROM2沉默上调活性氧、丙二醛、铁、Fe2+，下调SLC7A11、GPX4和谷胱甘肽水平。AKT或AKT激动剂（SC79）的过表达逆转了PROM2沉默对BC细胞糖酵解和铁凋亡的影响。我们的研究结果表明，PROM2是一种致癌基因，通过AKT/mTOR信号通路促进糖酵解和抑制铁凋亡，从而支持BC的进展。因此，PROM2可能是BC治疗的潜在治疗靶点。

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引用次数: 0

Calcium-dependent regulation of physiological vs pathological cardiomyocyte hypertrophy 生理性与病理性心肌细胞肥大的钙依赖性调节。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-08-15 DOI: 10.1016/j.bbamcr.2025.120046

Joshua Chung , Nathan Isles , Stuart Johnston , David J. Collins , Julie R. McMullen , H. Llewelyn Roderick , Vijay Rajagopal

Cardiomyocyte hypertrophic growth contributes to the adaptative response of the heart to meet sustained increases in hemodynamic demand. While hypertrophic responses to physiological cues maintains or enhances cardiac function, when triggered by pathological cues, this response is maladaptive, associated with compromised heart function, although initially, this response maybe adaptive with preserved function. Since cues and activated pathways associated with both forms of hypertrophy overlap, the question arises as to the mechanism that determines these different outcomes. Here we evaluate the hypothesis that cardiomyocyte Ca²⁺ signalling – a regulator of pathological hypertrophy – also signals physiological hypertrophy. We discuss how different Ca²⁺ profiles, in distinct subcellular organelles/microdomains, and interacting with other signalling pathways, provide a mechanism for Ca²⁺ to be decoded to induce distinct hypertrophic phenotypes. We discuss how integration of computational with rich structural and functional cellular measurements can be used to decipher the role of Ca²⁺ in hypertrophic gene programming.

心肌细胞肥厚性生长有助于心脏的适应性反应，以满足持续增加的血流动力学需求。虽然对生理信号的肥厚反应维持或增强了心功能，但当被病理信号触发时，这种反应是不适应的，与心功能受损有关，尽管最初，这种反应可能是适应性的，保留了功能。由于与两种形式的肥大相关的信号和激活通路重叠，因此决定这些不同结果的机制就产生了问题。在这里，我们评估假设心肌细胞Ca2+信号-病理肥大的调节-也信号生理肥大。我们讨论了不同的Ca2+谱，在不同的亚细胞细胞器/微域，并与其他信号通路相互作用，如何提供Ca2+被解码的机制，以诱导不同的肥厚表型。我们讨论如何集成计算与丰富的结构和功能细胞测量可以用来破译Ca2+在肥厚基因编程中的作用。

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引用次数: 0

SYT13: An underestimated synaptotagmin SYT13：一种被低估的突触联合蛋白

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-07-30 DOI: 10.1016/j.bbamcr.2025.120031

Johannes Lehmann , Alberto Catanese

Synaptotagmin-13 (SYT13) is a non-canonical member of the of synaptotagmin family that, canonical synaptotagmins, doesn't contain Ca²⁺ binding sites, but still appears to play a key role in the control of different cellular processes such as vesicle transport, cell migration, signaling and cell development. The recent findings associate SYT13 with neuronal survival and development, metabolic homeostasis (especially insulin secretion) and both oncogenic and tumor suppressive function in multiple cancers. And yet all this data is scattered in fields, with no systematic review covering SYT13's detailed biology. A comprehensive literature review is therefore needed to explain SYT13's multifaceted roles, uncover informational gaps and direct future studies to exploit SYT13 as a target for neurodegeneration, metabolic disease and cancer therapy.

SYT13 （synaptotagmin -13）是synaptotagmin家族的非规范成员，不含Ca2+结合位点，但仍在控制不同的细胞过程中发挥关键作用，如囊泡运输、细胞迁移、信号传导和细胞发育。最近的研究结果将SYT13与多种癌症的神经元存活和发育、代谢稳态（特别是胰岛素分泌）以及致癌和肿瘤抑制功能联系起来。然而，所有这些数据都分散在各个领域，没有对SYT13的详细生物学进行系统回顾。因此，需要全面的文献综述来解释SYT13的多方面作用，揭示信息空白，并指导未来的研究，以利用SYT13作为神经退行性疾病、代谢性疾病和癌症治疗的靶点。

引用次数: 0

Heat shock protein 70 regulates m6A modification in response to heat shock in esophageal squamous cell carcinoma. 热休克蛋白70在食管鳞状细胞癌热休克反应中调控m6A修饰。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-07-24 DOI: 10.1016/j.bbamcr.2025.120027

Bin Du, Jia Wang, Jun Ma, Pu Wang

Heat shock has been known to induce hyperplasia in esophageal epithelial cells. It is widely considered as a crucial risk factor in the initiation and development of esophageal squamous cell carcinoma (ESCC), yet our understanding of the underlying mechanisms remains limited. The m6A modification of mRNA plays a role in mediating several cellular processes and is critical during cell stress. Our study revealed that inhibiting of m6A 'writer' components of ESCC cells exhibit higher death rates and slower recovery after heat shock. After normalization using mRNA expression profiles, 91.08 % of significantly changed m6A modifications aligned with corresponding mRNA abundance changes, with no evidence of over-modification, while the increase in m6A modification of 8.92 % of heat-shock associated genes far exceeded the increase in mRNA (hyper - m6A modification), and A/U rich motifs were commonly observed in the 3'UTR of these gene. Inside the nucleus, the binding of HSP70s in m6A writer complex promote the hyper - m6A modification in specific mRNAs after heat shock. The stronger nuclear localization of HSP70 in ESCC tissues correlates with a poor prognosis for the patients. In conclusion, our research revealed that the nuclear HSP70 protein could bind to the METTL3/14 writer complex and regulate mRNA's m6A modification. Our results provide a new perspective for research into how HSP70 protein regulates mRNA stability and suggests a new direction for the comprehensive prevention and treatment of ESCC.

已知热休克可诱导食管上皮细胞增生。它被广泛认为是食管鳞状细胞癌（ESCC）发生和发展的关键危险因素，但我们对其潜在机制的了解仍然有限。mRNA的m6A修饰在介导几种细胞过程中起作用，在细胞应激过程中起关键作用。我们的研究表明，严重缺乏m6A ‘writer’成分的ESCC细胞在热休克后表现出更高的凋亡率和更慢的恢复速度。对mRNA表达谱进行归一化后，91.07 %的m6A修饰显著变化与相应的mRNA丰度变化一致，没有过度修饰的证据，而8.92 %的热休克相关基因m6A修饰的增加远远超过mRNA的增加（超m6A修饰），并且在这些基因的3'UTR中普遍观察到A/U富基序。在细胞核内，hsp70在m6A写入复合体中的结合促进了热休克后特定mrna的超m6A修饰。ESCC组织中HSP70的核定位越强，患者预后越差。综上所述，我们的研究揭示了核HSP70蛋白可以结合METTL3/14复合体并调节mRNA的m6A修饰。本研究结果为研究HSP70蛋白调控mRNA稳定性提供了新的视角，为ESCC的综合防治提供了新的方向。

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引用次数: 0

TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy TXNIP通过NCOA4介导的铁蛋白自噬促进铁凋亡。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-09-04 DOI: 10.1016/j.bbamcr.2025.120054

Pandian Nagakannan , Md Imamul Islam , Shakila Sultana , Soheila Karimi-Abdolrezaee , Eftekhar Eftekharpour

Ferroptosis is a recently discovered lytic form of cell death that is triggered by iron-driven excessive lipid peroxidation and depletion of glutathione and glutathione peroxidase-4 (GPX4). This form of cell death has been linked to a wide range of conditions from cancer to neurodegenerative diseases. Using murine hippocampal HT22 neurons, we aimed to investigate the underlying mechanisms of glutamate-mediated ferroptosis. A robust increase in Thioredoxin-Inhibiting Protein (TXNIP) prompted us to use genetic approaches and examine the role of this protein in ferroptosis in HT22 neurons, mouse embryonic fibroblasts, and Hela cells. Our results indicate that TXNIP is a key player in ferroptotic pathway, as its deletion conferred resistance to classic ferroptosis-inducing agents (erastin, RSL3, and ML210), while TXNIP overexpression increased their susceptibility to ferroptosis. Notably, TXNIP deletion protected cells from mitochondrial dysfunction induced by ferroptotic agents, independent of GSH and GPX4 levels. We further showed that TXNIP mediates ferroptosis through facilitating degradation of the iron-binding protein ferritin via NCOA4-mediated ferritinophagy. This resulted in elevated cytosolic labile iron levels, therefore amplifying lipid peroxidation, and promoting ferroptosis. Our findings suggest that TXNIP acts as a positive regulator of ferroptosis by modulating autophagy and iron availability. Targeting TXNIP might hold promise in developing drugs for diseases involving the ferroptotic pathway.

Ferroptosis是最近发现的一种细胞死亡的溶解形式，由铁驱动的过度脂质过氧化和谷胱甘肽和谷胱甘肽过氧化物酶-4 （GPX4）的消耗引发。这种形式的细胞死亡与从癌症到神经退行性疾病的广泛疾病有关。利用小鼠海马HT22神经元，我们旨在探讨谷氨酸介导的铁下垂的潜在机制。硫氧还蛋白抑制蛋白（TXNIP）的显著增加促使我们使用遗传方法并检测该蛋白在HT22神经元、小鼠胚胎成纤维细胞和Hela细胞中铁凋亡中的作用。我们的研究结果表明，TXNIP是铁凋亡途径的关键参与者，因为它的缺失使其对经典的铁凋亡诱导药物（erastin， RSL3和ML210）产生抗性，而TXNIP的过表达增加了它们对铁凋亡的易感性。值得注意的是，TXNIP缺失可以保护细胞免受不依赖于GSH和GPX4水平的致铁剂诱导的线粒体功能障碍。我们进一步表明，TXNIP通过ncoa4介导的铁蛋白噬噬促进铁结合蛋白铁蛋白的降解，从而介导铁凋亡。这导致细胞质不稳定铁水平升高，因此放大脂质过氧化，并促进铁下垂。我们的研究结果表明，TXNIP通过调节自噬和铁的可用性作为铁凋亡的积极调节剂。以TXNIP为靶点，可能为开发涉及铁致凋亡途径的疾病的药物带来希望。

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引用次数: 0

Hyperosmolarity-induced activation of PIEZO1 engages detrimental calcium/oxidative stress signaling and adaptive catalase response in renal inner medullary collecting duct (mIMCD3) cells 高渗透压诱导的PIEZO1激活在肾髓内收集管（mIMCD3）细胞中参与有害的钙/氧化应激信号和适应性过氧化氢酶反应。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-12-01 Epub Date: 2025-08-07 DOI: 10.1016/j.bbamcr.2025.120041

Stephanie Probst , Nadiya Romanova , Robin Herbrechter , Teresa Kern , Marie Bergmeier , Wing-Kee Lee , Frank Thévenod

The collecting duct (CD) is the final segment of the renal nephron and is involved in the fine regulation of osmotic and ionic homeostasis. Its medullary segment is continuously exposed to a wide spectrum of osmotic gradients and resultant osmotic stress. Strikingly, the expression of the mechanically activated non-selective cationic and Ca²⁺-permeable transduction ion channel PIEZO1 is most prominent in inner medullary CD (IMCD) cells, yet its functions there are still not well understood. We hypothesized increased PIEZO1 expression in the IMCD could be linked to its hyperosmotic stress environment. Using the mouse mIMCD₃ cell line, which has been used to characterize hyperosmotic stress-induced cell death, we demonstrate twice as much PIEZO1 expression compared to proximal tubule (WKPT-0293 Cl.2) or cortical CD (mCCD(cl.1)) cell lines. Hyperosmolarity/−tonicity by addition of NaCl ± urea to the culture medium (+ 100–300 mosmol/l) or PIEZO1 agonist Yoda1 (20 μmol/l) decreased mIMCD₃ cell viability assayed by MTT, which were antagonized by PIEZO1 inhibitors GsMTx4 (2.5 μmol/l) and salvianolic acid (SalB, 10 μmol/l). PIEZO1 activation by hyperosmolarity and agonists (Yoda1, Jedi1) increased Ca²⁺ influx, downstream reactive oxygen species (ROS), in particular mitochondrial superoxide (O₂^•-) formation, and subsequent adaptive ROS-decomposing catalase expression and activity that were sensitive to PIEZO1 antagonists (GsMTx4, SalB). Hence, the data demonstrate hyperosmolarity/−tonicity of the kidney elicits PIEZO1 activation, mitochondrial ROS formation and cell death that are partially countered by catalase-mediated stress adaptation.

集合管是肾元的最后一段，参与渗透和离子稳态的精细调节。它的髓质段持续暴露于广泛的渗透梯度和由此产生的渗透应力。引人注目的是，机械激活的非选择性阳离子和Ca2+渗透性转导离子通道PIEZO1的表达在髓内CD （IMCD）细胞中最为突出，但其功能仍未得到很好的理解。我们假设在IMCD中增加的PIEZO1表达可能与其高渗应激环境有关。使用小鼠mIMCD3细胞系（已用于表征高渗应激诱导的细胞死亡），我们证明PIEZO1的表达量是近端小管（WKPT-0293 Cl.2）或皮质CD（mCCD(cl.1)）细胞系的两倍。采用MTT法测定，在培养基（+100-300 μmol/l）或PIEZO1激动剂Yoda1（20 μmol/l）中加入NaCl±尿素的高渗透性/-强直性可降低mIMCD3细胞活力，而PIEZO1抑制剂GsMTx4（2.5 μmol/l）和丹酚酸（SalB, 10 μmol/l）可拮抗细胞活力。高渗透压和激动剂（Yoda1, Jedi1）激活PIEZO1会增加Ca2+内流，下游活性氧（ROS），特别是线粒体超氧化物（O2•-）的形成，以及随后对PIEZO1拮抗剂（GsMTx4, SalB）敏感的适应性ROS分解过氧化氢酶的表达和活性。因此，数据表明，肾脏的高渗透压/-强直性引发PIEZO1激活，线粒体ROS形成和细胞死亡，部分被过氧化氢酶介导的应激适应所抵消。

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