Biochimica et biophysica acta. Molecular cell research最新文献_第8页

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 : 2025-09-04 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

S100A16 knockdown reduces RPN2 expression and inhibits β-catenin/TCF signaling, leading to suppressed metastasis in cervical cancer cells S100A16敲低可降低RPN2表达，抑制β-catenin/TCF信号，抑制宫颈癌细胞转移

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-02 DOI: 10.1016/j.bbamcr.2025.120053

Min-Chieh Hsin , Po-Hui Wang , Pei-Ni Chen , Yi-Hsien Hsieh , Shun-Fa Yang , Chung-Yuan Lee

S100 calcium-binding protein A16 (S100A16), the most recently identified member of the S100 calcium-binding protein family, has been implicated in various cancers. However, its specific role in cervical cancer remains unclear. In this study, we demonstrated that silencing the S100A16 gene inhibits the migratory ability of HeLa and SiHa cells without affecting their viability. RNA sequencing analysis revealed that S100A16 significantly regulates ribophorin II (RPN2). Furthermore, RPN2 knockdown alone effectively suppressed cell migration and overexpression of S100A16 reversed the inhibition of migration caused by RPN2 silencing. Mechanistically, S100A16 was observed to regulate RPN2 through phosphorylated signal transducer and activator of transcription 3 (p-STAT3), which, in turn, modulated the downstream β-catenin/TCF pathway via phosphorylated GSK3β. An analysis of nuclear and cytosolic protein fractions further indicated that S100A16 silencing reduces the ability of β-catenin to translocate into the nucleus. In conclusion, our research revealed that S100A16 silencing downregulated RPN2 levels through p-STAT3, thereby inhibiting the p-GSK3β/β-catenin/TCF signaling pathway. These findings highlight S100A16 as a potential therapeutic target for cervical cancer.

S100钙结合蛋白A16 （S100A16）是最近发现的S100钙结合蛋白家族成员，与多种癌症有关。然而，它在宫颈癌中的具体作用尚不清楚。在本研究中，我们证明沉默S100A16基因可以抑制HeLa和SiHa细胞的迁移能力，而不影响其生存能力。RNA测序分析显示，S100A16显著调控核糖磷酸化蛋白II （ribophorin II, RPN2）。此外，单独敲低RPN2可有效抑制细胞迁移，过表达S100A16可逆转RPN2沉默导致的细胞迁移抑制。机制上，S100A16通过磷酸化的信号转导和转录激活因子3 （p-STAT3）调节RPN2，而RPN2又通过磷酸化的GSK3β调节下游的β-catenin/TCF通路。细胞核和细胞质蛋白的分析进一步表明，S100A16沉默降低了β-catenin转运到细胞核的能力。综上所述，我们的研究发现S100A16沉默通过p-STAT3下调RPN2水平，从而抑制p-GSK3β/β-catenin/TCF信号通路。这些发现强调S100A16是宫颈癌的潜在治疗靶点。

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引用次数: 0

Corrigendum to “Protein synthesis inhibition promotes nitric oxide generation and activation of CGKII-dependent downstream signaling pathways in the retina” [Biochim. Biophys. Acta (BBA) Mol. Cell Res. 1867 (2020) 118732 10.1016/j.bbamcr.2020.118732] “蛋白质合成抑制促进一氧化氮的产生和视网膜中cgkii依赖的下游信号通路的激活”[biochem]的更正。Biophys。[j].中国生物医学工程学报，2016,32(1):1 - 2。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-01 DOI: 10.1016/j.bbamcr.2025.120050

Marcelo Cossenza , Renato Socodato , Telmo A. Mejía-García , Ivan Domith , Camila C. Portugal , Luis F.H. Gladulich , Aline T. Duarte-Silva , Latika Khatri , Shannon Antoine , Franz Hofmann , Edward B. Ziff , Roberto Paes-de-Carvalho

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 : 2025-08-30 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

Unexplored gene PHKA1 interplays between glucose metabolism and breast cancer 未被发现的基因PHKA1在葡萄糖代谢和乳腺癌之间相互作用。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-08-27 DOI: 10.1016/j.bbamcr.2025.120052

Sweta H. Makwana , Jyoti Poswal , Pooja Yadav , Shailendra P. Singh , Chandi C. Mandal

Cancer cells often undergo metabolic reprogramming, typically increasing their uptake and utilization of energy sources like glucose, fatty acids, lactate, glutamine, and pyruvate, while maintaining redox balance. Rather than relying on oxidative phosphorylation, cancer cells preferentially engage glycolysis to convert pyruvate into lactate. This metabolic reprogramming correlates with altered glucose metabolism and dysregulated insulin signalling. Diabetes is associated with increased risk of certain cancer types. Cancer database analysis of genes involved in glucose metabolism, insulin signalling and diabetes, identified an unexplored differentially expressed PHKA1 gene associated with poor patient survivability in breast cancer. Expression of the PHKA1 gene was found to be upregulated under an environment of high glucose and insulin in cancer cells. Silencing PHKA1 via siRNA led to marked decrease in proliferative, invasion, migratory, and stem-like properties of MDA-MB-231 and MCF-7 breast cancer cells. Experimental findings demonstrated reduced expression of mesenchymal markers (e.g., Vimentin, Zeb-1/2), cell cycle markers (e.g., CDK-2/4), and proliferative markers (e.g., Bcl-2 and Bcl-xl), while expression of epithelial markers (e.g., E-cadherin and Keratin-19) were enhanced in PHKA1 knockdown cells when compared to control. Performance of glycolysis stress and mito stress assay further demonstrated that siPHKA1 cells had diminished glycolytic activity alongside suppressed mitochondrial function. These findings highlight intricate relationship between metabolic dysregulation observed in diabetes, contributing to the progression of cancer. Collectively, these observations highlight PHKA1 as an oncogenic candidate with potential role in breast cancer. Comprehensive understanding of such metabolic alterations is critical to designing targeted therapeutic strategies aimed at mitigating breast cancer progression.

癌细胞经常经历代谢重编程，通常会增加对葡萄糖、脂肪酸、乳酸、谷氨酰胺和丙酮酸等能量来源的摄取和利用，同时保持氧化还原平衡。癌细胞不依赖于氧化磷酸化，而是优先进行糖酵解，将丙酮酸转化为乳酸。这种代谢重编程与葡萄糖代谢改变和胰岛素信号失调有关。糖尿病会增加患某些癌症的风险。通过对葡萄糖代谢、胰岛素信号传导和糖尿病相关基因的癌症数据库分析，发现了一种未被发现的差异表达的PHKA1基因，该基因与乳腺癌患者生存能力差有关。PHKA1基因在高葡萄糖和胰岛素环境下被发现在癌细胞中表达上调。通过siRNA沉默PHKA1导致MDA-MB-231和MCF-7乳腺癌细胞的增殖、侵袭、迁移和干细胞样特性显著降低。实验结果显示，与对照组相比，PHKA1敲除细胞中间充质标记物（如Vimentin、Zeb-1/2）、细胞周期标记物（如CDK-2/4）和增殖标记物（如Bcl-2和Bcl-xl）的表达降低，而上皮标记物（如E-cadherin和Keratin-19）的表达增强。糖酵解应激和线粒体应激实验进一步表明，siPHKA1细胞糖酵解活性降低，线粒体功能受到抑制。这些发现强调了在糖尿病中观察到的代谢失调与癌症进展之间的复杂关系。总的来说，这些观察结果突出了PHKA1在乳腺癌中具有潜在的致癌作用。全面了解这种代谢改变对于设计旨在缓解乳腺癌进展的靶向治疗策略至关重要。

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引用次数: 0

The late stages of yeast mitoribosome large subunit biogenesis 酵母线粒体大亚基生物发生的后期

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-08-25 DOI: 10.1016/j.bbamcr.2025.120051

Sorbhi Rathore , Julian Conrad , Dasmanthie De Silva , Alberto Ferrari , Danielle Bouquio , Hyung-Jun Kim , Roger Salvatori , Andreas Linden , Olexandr Dybkov , Henning Urlaub , Martin Ott , Antoni Barrientos

The Saccharomyces cerevisiae mitoribosome synthesizes eight mitochondrial DNA-encoded proteins essential for oxidative phosphorylation. Mitoribosome large subunit (mtLSU) biogenesis involves the conserved DEAD-box helicase Mrh4 and the GTPases Mtg1/GTPBP7 and Mtg2/GTPBP5. Here, we have employed genetic, biochemical, in vitro reconstitution, and cryo-EM approaches to elucidate their hierarchical action during the late stages of mtLSU assembly. We show that Mrh4-mediated bL33m incorporation precedes Mtg1 recruitment to the 21S rRNA. Cryo-EM structures of mitoribosome assembly intermediates accumulating in the absence of Mtg1 or uL16m reveal that Mtg1 restructures the 21S rRNA H73-75 and H93 domains to their mature fold. This subsequently allows the structuring of neighboring peptidyl transfer center region helices and the incorporation of uL6m, uL16m, bL35m, and bL36m during late mtLSU maturation. Unexpectedly, monosomes containing immature mtLSU assemble in Mrh4-, bL33m-, uL16m-, Mtg1-, and Mtg2-depleted mitochondria, at levels that increase with the maturation state of the mtLSU particle. Our data have shed light on the rRNA folding events and the structuring of the MRPs that occur during the late stages of assembly. They have provided insight into the roles of assembly factors Mrh4, Mtg1, and Mtg2 during the process and revealed evolutionarily conserved mechanisms underlying mitochondrial ribosome assembly.

酿酒酵母菌线粒体核糖体合成八种线粒体dna编码的氧化磷酸化所必需的蛋白质。线粒体大亚基（mtLSU）的生物发生涉及保守的DEAD-box解旋酶Mrh4和gtpase Mtg1/GTPBP7和Mtg2/GTPBP5。在这里，我们采用了遗传、生化、体外重构和低温电镜等方法来阐明它们在mtLSU组装后期的分层作用。我们发现mrh4介导的bL33m掺入先于Mtg1募集到21S rRNA。在缺乏Mtg1或uL16m的情况下积累的线粒体组装中间体的低温电镜结构显示，Mtg1将21S rRNA H73-75和H93结构域重组到成熟褶皱。这随后使得邻近肽基转移中心区域螺旋的结构和uL6m、uL16m、bL35m和bL36m在mtLSU成熟后期的结合成为可能。出乎意料的是，含有未成熟mtLSU的单体在Mrh4-、bL33m-、uL16m-、Mtg1-和mtg2缺失的线粒体中组装，其水平随着mtLSU颗粒的成熟状态而增加。我们的数据揭示了在组装后期发生的rRNA折叠事件和mrp的结构。他们已经深入了解了装配因子Mrh4、Mtg1和Mtg2在这一过程中的作用，并揭示了线粒体核糖体组装的进化保守机制。

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引用次数: 0

Multiple roles of EML1 in microtubule stabilization and vesicle transport in the nervous system EML1在神经系统微管稳定和囊泡运输中的多重作用

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-08-24 DOI: 10.1016/j.bbamcr.2025.120048

Yufang Zhang , Jing Yu , Yao Zhou , Yan Yue , Yan Liu

Microtubule-associated protein EML1 is an important member of the EML family and plays a key role in cytoskeleton regulation and neural development. During neural development, EML1 expression is spatiotemporally specific, and its functional abnormalities are closely associated with neural developmental disorders such as subcortical band heterotopia. This article systematically reviews the structural characteristics and biological functions of EML1. Structural studies have shown that EML1 contains unique HELP-WD and TAPE domains, which underlie its binding to microtubules and functional performance. Functionally, EML1 regulates microtubule stability through multiple mechanisms. Moreover, EML1 is also involved in regulating intracellular material transport—maintaining the stability of transport tracks, coordinating the function of motor proteins, and regulating Golgi-related transport. These findings reveal the multiple roles of EML1 in cellular physiological processes and provide a new perspective for understanding the pathogenesis of related diseases. Future research should focus on elucidating the precise EML1 action mechanisms and its potential as a therapeutic target.

微管相关蛋白EML1是EML家族的重要成员，在细胞骨架调控和神经发育中起关键作用。在神经发育过程中，EML1的表达具有时空特异性，其功能异常与皮层下带异位等神经发育障碍密切相关。本文系统综述了EML1的结构特点和生物学功能。结构研究表明，EML1含有独特的HELP-WD和TAPE结构域，这是其与微管结合和功能性能的基础。在功能上，EML1通过多种机制调节微管稳定性。此外，EML1还参与调节细胞内物质运输——维持运输路径的稳定性，协调运动蛋白的功能，调节高尔基相关运输。这些发现揭示了EML1在细胞生理过程中的多重作用，为理解相关疾病的发病机制提供了新的视角。未来的研究应集中于阐明EML1的确切作用机制及其作为治疗靶点的潜力。

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引用次数: 0

CHIP modulates Wnt/β-catenin signalling in colorectal cancer through proteasomal degradation of DDX17 CHIP通过蛋白酶体降解DDX17调节结直肠癌中Wnt/β-catenin信号

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-08-22 DOI: 10.1016/j.bbamcr.2025.120049

Sunny Kumar , Sayani Ghosh , Malini Basu , Mrinal K. Ghosh

The C-terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, plays a pivotal role in cellular protein homeostasis by targeting client proteins for proteasomal degradation. DEAD-box RNA helicase DDX17 is a key regulator of RNA metabolism and has been implicated in various cancer-related processes, including Wnt/β-catenin signalling and EMT. In this study, we uncover a novel regulatory axis involving CHIP and DDX17 responsible for modulation of Wnt/β-catenin signalling in colorectal cancer (CRC). Bioinformatic analyses of CPTAC database and immunohistochemical analysis of clinical samples revealed a significant negative correlation between CHIP and DDX17. By using immunoprecipitation-mass spectrometry we have identified DDX17 as a high-confidence interacting partner of CHIP, which was validated through co-immunoprecipitation, domain-mapping, immunocytochemistry, and molecular docking studies, pinpointing the TPR domain of CHIP is essential for this interaction. Mechanistically, CHIP overexpression led to accelerated degradation of DDX17, resulting in reduced β-catenin mRNA stability, leading to the suppression of Wnt/β-catenin signalling that results in G1 arrest and decreasing proliferation and EMT. Conversely, CHIP knockdown stabilized DDX17, hence promoting β-catenin signalling that leads to oncogenic phenotype. Our results suggest that CHIP exerts a tumor-suppressive phenotype in CRC by destruction of DDX17, thereby attenuating β-catenin-driven oncogenic processes. Altogether, this study identifies a novel “CHIP–DDX17–β-catenin” axis as a critical regulatory mechanism in CRC.

hsc70相互作用蛋白（CHIP）的c端是一种E3泛素连接酶，通过靶向客户蛋白进行蛋白酶体降解，在细胞蛋白稳态中起关键作用。DEAD-box RNA解旋酶DDX17是RNA代谢的关键调节因子，参与多种癌症相关过程，包括Wnt/β-catenin信号传导和EMT。在这项研究中，我们发现了一个涉及CHIP和DDX17的新的调控轴，负责调节结直肠癌（CRC）中Wnt/β-catenin信号传导。CPTAC数据库的生物信息学分析和临床样本的免疫组织化学分析显示CHIP与DDX17呈显著负相关。通过免疫沉淀-质谱法，我们确定了DDX17是CHIP的高置信度相互作用伙伴，通过共免疫沉淀、结构域定位、免疫细胞化学和分子对接研究验证了这一点，确定CHIP的TPR结构域对这种相互作用至关重要。从机制上讲，CHIP过表达导致DDX17降解加速，导致β-catenin mRNA稳定性降低，从而抑制Wnt/β-catenin信号传导，导致G1阻滞，减少增殖和EMT。相反，CHIP敲除稳定了DDX17，从而促进了导致致癌表型的β-catenin信号传导。我们的研究结果表明，CHIP通过破坏DDX17在CRC中发挥肿瘤抑制表型，从而减弱β-catenin驱动的致癌过程。总之，本研究确定了一个新的“CHIP-DDX17 -β-catenin”轴作为CRC的关键调控机制。

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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 : 2025-08-16 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

Corrigendum to “A fluorescent protein C-terminal fusion knock-in is functional with TRPA1 but not TRPC5” [Biochim. Biophys. Acta Mol. Cell Res. 1872(2) (2025) 119887] “一种荧光蛋白c端融合敲入对TRPA1起作用，但对TRPC5不起作用”的更正[biochem]。Biophys。分子细胞学报，1872(2)(2025)[19887]。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-08-15 DOI: 10.1016/j.bbamcr.2025.120042

Aaron Tragl , Alexandra Ptakova , Viktor Sinica , Rathej Meerupally , Christine König , Carolina Roza , Ivan Barvík , Viktorie Vlachova , Katharina Zimmermann

引用次数: 0