Biochimica et biophysica acta. Molecular basis of disease最新文献_第4页

Vimentin-targeting adaptogen withaferin A: Potential to selectively suppress cervical cancer – Single-cell microspectroscopic and molecular analysis 靶向vimentin的适应原与aferin A：选择性抑制宫颈癌的潜力-单细胞显微光谱和分子分析

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-25 DOI: 10.1016/j.bbadis.2025.168125

Ewa Pięta , Agnieszka Panek , Monika Szczepanek-Dulska , Katarzyna Pogoda

This study investigates the preferential anticancer effects of withaferin A, an adaptogenic compound, on primary and metastatic cervical cancer cells (C-33 A and CaSki, respectively) and non-cancerous skin fibroblast cells (Detroit-551). Employing a multi-modal approach, we combined biological assays with advanced vibrational spectroscopic imaging techniques, including Fourier-transform infrared (FT-IR), Raman (RS), and atomic force microscopy (AFM). The results revealed a dose-dependent reduction in cell viability, with a more pronounced effect observed in C-33 A cells compared to CaSki and fibroblasts, indicating a heightened sensitivity of C-33 A cells to withaferin A. The comet assay revealed significantly higher levels of DNA damage in primary tumor C-33A cells, whereas minimal DNA breaks were observed in fibroblasts and metastatic cells, further confirming the higher sensitivity of cancer cells compared to fibroblasts. Fluorescence staining and AFM topography imaging showed morphological alterations in cancer cells at higher withaferin A doses and longer incubation times. Flow cytometry analysis revealed significant apoptotic changes in primary C-33A cells due to withaferin A treatment, highlighting a large amount of cells undergoing late apoptosis, compared to a weaker apoptotic effect on metastatic CaSki cells and negligible effect for fibroblasts. Spectroscopic analyses revealed molecular alterations in lipid, protein, and nucleic acid composition, indicative of withaferin A's impact on cellular membranes and genetic material. These findings highlight withaferin A as a promising therapeutic agent with the potential to preferentially target primary cervical cancer cells, while minimizing toxicity to healthy cells.

本研究探讨了一种适应性化合物withaferin A对原发性和转移性宫颈癌细胞（分别为c - 33a和CaSki）和非癌性皮肤成纤维细胞（Detroit-551）的优先抗癌作用。采用多模态方法，我们将生物检测与先进的振动光谱成像技术相结合，包括傅里叶变换红外（FT-IR）、拉曼（RS）和原子力显微镜（AFM）。结果显示，与CaSki和成纤维细胞相比，在C-33A细胞中观察到的效果更明显，表明C-33A细胞对withaferin a的敏感性更高。彗星试验显示，原发肿瘤C-33A细胞的DNA损伤水平显著较高，而在成纤维细胞和转移细胞中观察到的DNA断裂最小，进一步证实了癌细胞比成纤维细胞更高的敏感性。荧光染色和AFM形貌成像显示，在高剂量和较长孵育时间下，癌细胞的形态发生了变化。流式细胞术分析显示，原代C-33A细胞由于withaferin A处理而发生了显著的凋亡变化，显示大量细胞发生了晚期凋亡，而对转移性CaSki细胞的凋亡作用较弱，对成纤维细胞的影响可以忽略不计。光谱分析揭示了脂质、蛋白质和核酸组成的分子改变，表明了withaferin A对细胞膜和遗传物质的影响。这些发现突出了withaferin A作为一种有前途的治疗药物，具有优先靶向原发性宫颈癌细胞的潜力，同时将对健康细胞的毒性降到最低。

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引用次数: 0

Swimming exercise attenuates diabetic myopathy and is associated with histological and mitochondrial changes in pregnant rats (Rattus norvegicus) 游泳运动减轻妊娠大鼠糖尿病性肌病，并与组织学和线粒体变化有关（褐家鼠）

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-25 DOI: 10.1016/j.bbadis.2025.168126

Bruna Bologna Catinelli , Angélica Mércia Pascon Barbosa , Aline Medolago Carr , Rafael Guilen de Oliveira , Fernanda Cristina Bergamo Alves , Franciele Mosele , Agnaldo Bruno Chies , Sérgio Luis Felisbino , Luis Sobrevia , Patrícia de Souza Rossignoli , Marilza Vieira Cunha Rudge , Diamater Study Group

Aim

Diabetic-induced myopathy (DiM) is reversed by swimming exercise (SE) in diabetic pregnant rats. This study aims to characterise the role of muscle stem cells (MuSCs), mitochondrial adaptations, and inflammation in this process.

Methods

A mild hyperglycaemic pregnant rat model was created by administering 100 mg/kg streptozotocin to Wistar female newborns on the first day of life. In adulthood, after mating, the rats were assigned to either a sedentary or exercise group. The SE protocol involved 60 min of daily swimming, 6 days per week, from gestational day 0 to 20. On gestational day 21, blood samples, rectus abdominis muscle (RAM), and soleus muscle were collected for analysis of fiber type, MuSCs count, mitochondrial adaptations, and inflammation markers.

Results

The diabetic group showed a lower number of fast and slow-twitch fibers. SE increased the number of MuSCs, the MuSCs/myonuclei ratio, mitochondrial area, and count, and restored citrate synthase activity. SE also increased the MuSCs/fiber and myonuclei/fiber ratios, as well as the mitochondria number/fiber and mitochondria area/fiber ratios, showing a positive relationship between mitochondrial count and fiber number in the diabetic group. Inflammation analysis revealed no differences in pro-inflammatory marker expression or quantification.

Conclusion

These results highlight a new combined effect of SE, increasing MuSCs and mitochondrial number and area, as well as restoring citrate synthase activity, suggesting that changes in muscle histology, MuSCs abundance, and mitochondrial adaptations with SE in diabetic animals may be key mechanisms in attenuating RAM DiM in diabetic pregnant rats.

目的通过游泳运动（SE）逆转糖尿病妊娠大鼠糖尿病性肌病（DiM）。本研究旨在描述肌肉干细胞（MuSCs）、线粒体适应和炎症在这一过程中的作用。方法Wistar雌性新生儿出生第一天给予100 mg/kg链脲佐菌素，建立轻度高血糖妊娠大鼠模型。成年后，交配后，老鼠被分配到久坐组或运动组。SE方案包括每天游泳60分钟，每周6天，从妊娠第0天到第20天。在妊娠第21天，采集血液样本、腹直肌（RAM）和比目鱼肌，分析纤维类型、musc计数、线粒体适应性和炎症标志物。结果糖尿病组快、慢肌纤维数量明显减少。SE增加了MuSCs数量、MuSCs/myonuclei比值、线粒体面积和数量，恢复了柠檬酸合成酶活性。SE还增加了糖尿病组MuSCs/fiber和myonuclei/fiber比值，以及线粒体数目/fiber和线粒体面积/fiber比值，表明线粒体数目和纤维数目呈正相关。炎症分析显示，促炎标志物的表达和定量没有差异。结论SE对糖尿病妊娠大鼠的RAM DiM有新的联合作用，增加了MuSCs和线粒体的数量和面积，恢复了柠檬酸合酶的活性，提示SE对糖尿病动物肌肉组织学、MuSCs丰度和线粒体适应性的改变可能是糖尿病妊娠大鼠RAM DiM减轻的关键机制。

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引用次数: 0

Astragalus polysaccharide hinders cervical cancer immune escape by targeting NR3C2 and activating SLC40A1 黄芪多糖通过靶向NR3C2、激活SLC40A1抑制宫颈癌免疫逃逸

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-24 DOI: 10.1016/j.bbadis.2025.168123

Wenzhi Liu , Lu Zhang , Yixin Wang , Xiaohong Jiang , Jinting Tan , Ying Zhang , Yuanyuan Fu

Astragalus polysaccharides (APS) show promising effects in preventing tumor progression and immune escape. This study investigated the mechanism of APS in immune escape in cervical cancer (CC). The effects of different APS concentrations on the viability of CC cell lines (HeLa and SiHa) were determined. Immune evasion by CC cells was examined after APS treatment. An in vivo model was constructed by subcutaneous injection of U14 cells, and the effect of APS on immune evasion was investigated. APS downstream targets were screened using multiple databases, and the regulatory relationship between APS and NR3C2 was verified. Bioinformatics analysis was conducted to identify the downstream molecules of NR3C2, and the regulatory mechanism was validated. The effects of NR3C2 and SLC40A1 on immune escape were tested in vivo and in vitro. APS inhibited immune escape in CC and activated NR3C2 expression and CD8⁺ T cell function. NR3C2 knockdown reversed the inhibitory effects of APS on immune escape and malignant behaviors of CC cells. NR3C2 was enriched in the SLC40A1 promoter and promoted SLC40A1 expression. SLC40A1 upregulation enhanced the inhibitory effect of APS on immune escape in CC. APS inhibits immune escape of CC by targeting NR3C2 and activating SLC40A1.

黄芪多糖（Astragalus polysaccharides， APS）在预防肿瘤进展和免疫逃逸方面具有良好的作用。本研究探讨了APS在宫颈癌免疫逃逸中的作用机制。测定不同浓度APS对CC细胞株（HeLa和SiHa）活力的影响。APS处理后检测CC细胞的免疫逃避。通过皮下注射U14细胞建立体内模型，观察黄芪多糖对免疫逃逸的影响。通过多个数据库筛选APS下游靶点，验证APS与NR3C2之间的调控关系。通过生物信息学分析鉴定了NR3C2的下游分子，验证了其调控机制。体内外实验检测NR3C2和SLC40A1对免疫逃逸的影响。APS抑制CC细胞免疫逃逸，激活NR3C2表达和CD8+ T细胞功能。NR3C2敲低逆转了APS对CC细胞免疫逃逸和恶性行为的抑制作用。NR3C2富集于SLC40A1启动子中，促进SLC40A1的表达。SLC40A1上调增强了APS对CC免疫逃逸的抑制作用，APS通过靶向NR3C2激活SLC40A1抑制CC免疫逃逸。

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引用次数: 0

NR5A2 promotes epithelial-to-mesenchymal transition in renal fibrosis by targeting MMP25 transcription NR5A2通过靶向MMP25转录促进肾纤维化的上皮到间质转化

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-24 DOI: 10.1016/j.bbadis.2025.168121

Xiao Wang , Yinong Chang , Yong Qian , Wei min Shan , Guang Chen , Xiao-wei Li , Jie-hao Zhou

Renal fibrosis is a hallmark of chronic kidney disease (CKD), with epithelial–mesenchymal transition (EMT) recognized as a key contributing process. Here, we identify nuclear receptor NR5A2 as an important regulator that promotes EMT in renal tubular epithelial cells through transcriptional activation of MMP25. NR5A2 expression was consistently elevated in human fibrotic kidneys, a unilateral ureteral obstruction (UUO) mouse model, and TGF-β1–treated HK-2 cells. Both siRNA-mediated knockdown and pharmacological inhibition with ML-180 attenuated EMT markers and fibrotic responses. Mechanistically, NR5A2 directly bound to the MMP25 promoter, as demonstrated by luciferase reporter assays, ChIP–qPCR, and molecular docking analysis, while MMP25 silencing counteracted NR5A2-driven EMT. These findings suggest that the NR5A2–MMP25 axis contributes to renal fibrogenesis and may represent a potential therapeutic target for CKD.

肾纤维化是慢性肾脏疾病（CKD）的一个标志，上皮-间质转化（EMT）被认为是一个关键的促进过程。在这里，我们发现核受体NR5A2是一个重要的调节因子，通过MMP25的转录激活促进肾小管上皮细胞的EMT。NR5A2的表达在人纤维化肾、单侧输尿管梗阻（UUO）小鼠模型和TGF-β1处理的HK-2细胞中持续升高。sirna介导的敲除和ML-180的药理学抑制减弱了EMT标记和纤维化反应。荧光素酶报告基因检测、ChIP-qPCR和分子对接分析表明，从机制上讲，NR5A2直接与MMP25启动子结合，而MMP25沉默抵消了NR5A2驱动的EMT。这些发现表明NR5A2-MMP25轴参与肾脏纤维化，可能代表CKD的潜在治疗靶点。

引用次数: 0

USP38 deficiency mitigates arrhythmogenic remodeling in obese mice by inhibiting TLR4/CaMKII signaling USP38缺乏通过抑制TLR4/CaMKII信号传导减轻肥胖小鼠的心律失常重塑。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-21 DOI: 10.1016/j.bbadis.2025.168122

Tao Chen , Hongjie Yang , Yang Gong , Jingjing Zhang , He Huang , Wei Shuai

Obesity-associated metabolic disturbances and cardiac remodeling significantly contribute to ventricular arrhythmias (VAs), a leading cause of sudden cardiac death. Although our previous studies have implicated the deubiquitinase USP38 in cardiovascular pathology, its precise role in obesity-related VAs remains unclear. Here, we aimed to elucidate the functional role and underlying mechanisms of USP38 in obesity-induced VAs.Cardiac-specific Usp38 knockout (CKO) mice were commercially generated. Obesity was induced by feeding mice a high-fat diet (HFD), while control mice received a normal diet (ND). We found the USP38 expression was significantly elevated in cardiac tissues of obese mice. Cardiac-specific deletion of USP38 markedly improved metabolic profiles and attenuated pathological remodeling, evidenced by reduced fibrosis markers (α-SMA, collagen I, collagen III), hypertrophy markers (ANP, BNP, β-MHC), and aberrant ion channel expression (Cav1.2, Kv1.5, Kv2.1, Kv4.2, Kv4.3). Correspondingly, the incidence of inducible VAs was significantly reduced. Co-immunoprecipitation confirmed a direct interaction between USP38 and the Toll-like receptor-4 (TLR4) signaling pathway. Further analyses demonstrated that USP38 knockout effectively blunted TLR4-mediated CaMKII activation both in vivo and in vitro. Cardiac-specific USP38 knockout effectively mitigates obesity-induced cardiac hypertrophy, fibrosis, and electrical remodeling, significantly reducing susceptibility to ventricular arrhythmias via inhibition of the TLR4/CaMKII signaling pathway. Mechanically, USP38 interacts with TLR4 and prevents the proteasomal degradation of TLR4, stabilizing TLR4 and promoting the activation of its downstream mediators. Therefore, targeted inhibition of USP38 may represent a promising therapeutic strategy for preventing obesity-associated ventricular arrhythmias.

肥胖相关的代谢紊乱和心脏重构显著导致室性心律失常（VAs），这是心源性猝死的主要原因。尽管我们之前的研究表明去泛素酶USP38与心血管病理有关，但其在肥胖相关VAs中的确切作用尚不清楚。在此，我们旨在阐明USP38在肥胖诱导的VAs中的功能作用及其潜在机制。心脏特异性Usp38基因敲除（CKO）小鼠被商业化生产。给小鼠喂食高脂肪饮食（HFD）诱导肥胖，而对照组小鼠喂食正常饮食（ND）。我们发现肥胖小鼠心脏组织中USP38的表达显著升高。心脏特异性缺失USP38显著改善了代谢谱，减轻了病理性重塑，纤维化标志物（α-SMA、胶原I、胶原III）、肥大标志物（ANP、BNP、β-MHC）和异常离子通道表达（Cav1.2、Kv1.5、Kv2.1、Kv4.2、Kv4.3）的减少证明了这一点。相应的，诱导性VAs的发生率显著降低。共免疫沉淀证实了USP38与toll样受体-4 （TLR4）信号通路之间的直接相互作用。进一步的分析表明，USP38敲除在体内和体外都能有效地减弱tlr4介导的CaMKII激活。心脏特异性USP38基因敲除可有效减轻肥胖引起的心脏肥大、纤维化和电重构，通过抑制TLR4/CaMKII信号通路显著降低室性心律失常的易感性。机械上，USP38与TLR4相互作用，阻止TLR4的蛋白酶体降解，稳定TLR4并促进其下游介质的激活。因此，靶向抑制USP38可能是预防肥胖相关室性心律失常的一种有前景的治疗策略。

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引用次数: 0

Urolithin A protects against calcium oxalate-induced crystal formation and kidney injury by regulating PCK1 to restore mitophagy function in kidney stone disease 尿素A通过调节PCK1恢复肾结石的自噬功能，防止草酸钙诱导的晶体形成和肾损伤。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-19 DOI: 10.1016/j.bbadis.2025.168106

Xiaoyi Sun , Chunlin Gao , Pei Zhang , Yingchao Peng , Meiqiu Wang , Jiuyu Liu , Chenxi Ma , Shan Li , Zhengkun Xia

Kidney stone disease (KSD) is one of the most common urological disorders, and oxalate-induced tubular epithelial cell injury plays a crucial role in stone-related renal damage. However, the mechanisms linking oxalate exposure to mitochondrial dysfunction remain unclear.

Urolithin A (UA), a gut microbiota–derived metabolite of ellagitannins, is recognized for its antioxidant and mitophagy-promoting properties. This study investigated the renoprotective effects and mechanisms of UA in calcium oxalate (CaOx) crystal–induced renal injury. In mice, UA markedly reduced renal CaOx deposition, improved renal function, and alleviated kidney injury. Consistently, both in vivo and in vitro experiments demonstrated that UA restored oxalate-suppressed mitophagy while also alleviating oxidative stress, apoptosis, and mitochondrial dysfunction.

Transcriptomic and molecular docking analyses identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a downstream target of UA. UA restored PCK1 expression under oxalate stress both in vivo and in vitro, whereas pharmacological inhibition of PCK1 weakened the renal protective and mitophagy-promoting effects. Conversely, PCK1 overexpression enhanced mitophagy under high-oxalate conditions.

These findings indicate that UA alleviates CaOx-induced renal injury by activating PCK1-dependent mitophagy and restoring mitochondrial homeostasis. Given its natural origin and favorable safety profile, UA represents a promising candidate for preventing or treating calcium oxalate–associated renal injury.

肾结石病（KSD）是最常见的泌尿系统疾病之一，草酸盐诱导的肾小管上皮细胞损伤在结石相关性肾损害中起着至关重要的作用。然而，草酸暴露与线粒体功能障碍之间的联系机制尚不清楚。尿素A （UA）是一种肠道微生物衍生的鞣花单宁代谢物，被认为具有抗氧化和促进线粒体自噬的特性。本研究探讨了UA对草酸钙（CaOx）晶体所致肾损伤的保护作用及其机制。在小鼠中，UA可显著减少肾CaOx沉积，改善肾功能，减轻肾损伤。体内和体外实验一致表明，UA可以恢复草酸抑制的线粒体自噬，同时减轻氧化应激、细胞凋亡和线粒体功能障碍。转录组学和分子对接分析发现，磷酸烯醇丙酮酸羧激酶1 （PCK1）是UA的下游靶点。UA在体内和体外均能恢复草酸应激下PCK1的表达，而PCK1的药理抑制则削弱了其对肾脏的保护和促进有丝分裂的作用。相反，在高草酸条件下，PCK1过表达增强了线粒体自噬。这些结果表明，UA通过激活pck1依赖性的线粒体自噬和恢复线粒体稳态来减轻caox诱导的肾损伤。鉴于其天然来源和良好的安全性，UA代表了预防或治疗草酸钙相关肾损伤的有希望的候选者。

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引用次数: 0

Multifaceted role of primary cilia and ciliary proteins: A potential nexus for hedgehog signaling and prostate cancer 原发性纤毛和纤毛蛋白的多方面作用：刺猬信号和前列腺癌的潜在联系。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-14 DOI: 10.1016/j.bbadis.2025.168120

Jyoti B. Kaushal , Parthasarathy Seshacharyulu , Surinder K. Batra , Sakthivel Muniyan

The primary cilium is a solitary, non-motile, microtubule-based organelle that extends from the cell membrane and functions as a critical coordinator of multiple signaling pathways. Despite its association with hundreds of proteins, only a subset is essential for its biogenesis and signal transmission. Malfunctions in primary cilia are associated with developmental disorders and various malignancies, including prostate cancer (PCa). Recent studies highlight the regulation of ciliogenesis, cilia length, and interaction among cilia-resident proteins, particularly within the ciliary hedgehog (Hh) signaling axis in oncogenesis, thereby positioning primary cilia as potential therapeutic targets. Nevertheless, the precise contribution of ciliary components to Hh pathway modulation in PCa remains poorly defined. This review integrates emerging evidence to elucidate the current state of knowledge on the structural and functional attributes of primary cilia, cilia-mediated molecular dynamics with Hh signaling, and their intersection in the context of PCa progression, including prostate development, carcinogenesis, and tumor microenvironment dynamics. Particular emphasis is placed on cilia-associated proteins, such as SCL/TAL1 interrupting locus (STIL), intraflagellar transport (IFT) family proteins, ADP-ribosylation factor (Arf) family proteins, transforming acidic coiled-coil protein-3 (TACC3), mitotic kinase Aurora A, and dual-specificity tyrosine-regulated kinase (DYRK), which have been mechanistically linked to PCa and modulate Hh signaling. However, their detailed contributions remain insufficiently characterized and warrant further investigation. This review underscores the role of primary cilia in PCa progression, highlights unresolved mechanistic gaps in their regulation, and proposes future directions for targeted molecular and therapeutic research.

初级纤毛是一个孤立的、不运动的、基于微管的细胞器，从细胞膜延伸出来，作为多种信号通路的关键协调者。尽管它与数百种蛋白质相关，但只有一个子集对其生物发生和信号传递至关重要。原发性纤毛功能障碍与发育障碍和各种恶性肿瘤，包括前列腺癌（PCa）有关。最近的研究强调了纤毛发生、纤毛长度和纤毛驻留蛋白之间的相互作用的调节，特别是在纤毛hedgehog （Hh）信号轴中，从而将初级纤毛定位为潜在的治疗靶点。然而，纤毛成分对PCa中Hh通路调节的精确贡献仍然不明确。这篇综述整合了新出现的证据来阐明初级纤毛的结构和功能属性、纤毛介导的Hh信号分子动力学以及它们在前列腺癌进展（包括前列腺发育、致癌和肿瘤微环境动力学）背景下的交叉知识的现状。特别强调的是纤毛相关蛋白，如SCL/TAL1中断位点（STIL），鞭毛内运输（IFT）家族蛋白，adp -核糖化因子（Arf）家族蛋白，转化酸性卷曲蛋白-3 (TACC3)，有丝分裂激酶Aurora A和双特异性酪氨酸调节激酶（DYRK），它们与PCa有机制联系并调节Hh信号。然而，他们的详细贡献仍然没有得到充分的描述，需要进一步调查。这篇综述强调了初级纤毛在前列腺癌进展中的作用，强调了其调控中尚未解决的机制空白，并提出了靶向分子和治疗研究的未来方向。

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引用次数: 0

Inhibition of BRG1 suppresses the progression of glioblastoma via repressing oligodendrocyte genes 抑制BRG1通过抑制少突胶质细胞基因来抑制胶质母细胞瘤的进展。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-14 DOI: 10.1016/j.bbadis.2025.168118

Huanwen Rui , Bo Chen , Min Wang , Xing Xue , Yangyang Ma , Chenyang Zhang , Ying Xu , Zai Song , Feifei Ji , Weijun Feng , Hao Li

Glioblastoma, the most lethal and pervasive subtype of glioma, has been classified according to both molecular signatures and cell identity. However, the promise of subtype-specific therapy for GBM has yet to be realized. We hypothesize that epigenetic compounds could be effective due to the crucial role of epigenetic regulation in maintaining individual GBM subtypes. We establish a mouse GBM model by expressing AKT3, DN-p53 and PDGFB (ADP) in cortical neural progenitor cells via in utero electroporation. Gene expression analysis demonstrate that ADP glioma exhibits the oligodendrocyte precursor cell (OPC) signature. A small-scale compound screening conducted in cultured ADP tumor cells identify BRM014 (dual ATPase inhibitor of chromatin remodelers BRM/BRG1) as an effective compound. Mechanistically, acute treatment of ADP tumor cells with BRM014 specifically inhibits chromatin accessibility and the expression of oligodendrocyte genes. Importantly, genetic depletion of Brg1 significantly delays tumor progression and prolongs the survival of ADP glioma-bearing mice. Importantly, BRM014 treatment selectively inhibits the growth of human GBM cells with the OPC signature. In sum, our findings demonstrate that the inhibition of ATPase activity of BRG1 is a promising epigenetic therapy for OPC-like GBM.

胶质母细胞瘤是胶质瘤中最致命和最普遍的亚型，根据分子特征和细胞特性进行分类。然而，亚型特异性治疗GBM的前景尚未实现。我们假设，由于表观遗传调控在维持单个GBM亚型中的关键作用，表观遗传化合物可能是有效的。我们通过子宫内电穿孔在小鼠皮层神经祖细胞中表达AKT3、DN-p53和PDGFB (ADP)，建立小鼠GBM模型。基因表达分析表明ADP胶质瘤具有少突胶质前体细胞（OPC）特征。在培养的ADP肿瘤细胞中进行的小规模化合物筛选发现BRM014（染色质重塑者BRM/BRG1的双atp酶抑制剂）是一种有效的化合物。机制上，BRM014急性治疗ADP肿瘤细胞特异性抑制染色质可及性和少突胶质细胞基因的表达。重要的是，Brg1基因缺失可显著延缓ADP胶质瘤小鼠的肿瘤进展，延长其生存期。重要的是，BRM014治疗选择性地抑制具有OPC特征的人GBM细胞的生长。总之，我们的研究结果表明，抑制BRG1的atp酶活性是一种很有希望的opc样GBM的表观遗传学治疗方法。

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引用次数: 0

The KLKB1–TFE3–BRAF/MEK/ERK axis regulates neuronal ferroptosis in vascular dementia KLKB1-TFE3-BRAF/MEK/ERK轴调控血管性痴呆的神经元铁下垂。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-14 DOI: 10.1016/j.bbadis.2025.168119

Yan Su , Lingqi Kong , Bowen Xue , Peng Shi , Sheng Cai , Yang Xu , Xianwen Chen , Hongdang Qu

Background

Increasing evidence suggests that ferroptosis has significant implications for the pathogenesis of vascular dementia (VaD). Although KLKB1 exacerbates neurological damage in VaD by promoting ferroptosis, the exact mechanism remains unclear. The aim of this study is to elucidate the specific pathway through which KLKB1 mediates ferroptosis in VaD and to identify effective therapeutic strategies.

Methods

Rat models of VaD were constructed by bilateral common carotid artery occlusion (BCCAO). Behavioral impairment in VaD rats was assessed, along with pathological damage to hippocampal neurons. Transcriptome sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blotting, and quantitative real-time polymerase chain reaction (qPCR) were used to identify the downstream pathways through which KLKB1 regulates ferroptosis. Immunoprecipitation–mass spectrometry (IP–MS), protein–protein interaction networks, coimmunoprecipitation (Co-IP), and immunofluorescence assays were used to screen for proteins that interact with KLKB1.

Results

KLKB1 promotes ferroptosis in VaD model rats through its interaction with transcription factor E3 (TFE3). The knockdown of KLKB1 decreased TFE3 expression levels and suppressed ferroptosis through the inhibition of the BRaf/MEK/ERK signaling cascade. Consistent antiferroptotic effects were observed following TFE3 knockdown.

Conclusion

The KLKB1–TFE3–BRaf/MEK/ERK signaling axis represents a novel target for attenuating ferroptosis in VaD.

背景：越来越多的证据表明，铁下垂在血管性痴呆（VaD）的发病机制中具有重要意义。虽然KLKB1通过促进铁下垂加重VaD的神经损伤，但确切的机制尚不清楚。本研究的目的是阐明KLKB1介导VaD铁下垂的具体途径，并确定有效的治疗策略。方法：采用双侧颈总动脉闭塞法（BCCAO）建立VaD大鼠模型。评估VaD大鼠的行为障碍，以及海马神经元的病理损伤。转录组测序、基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析、Western blotting和定量实时聚合酶链反应（qPCR）用于鉴定KLKB1调控铁死亡的下游途径。免疫沉淀-质谱法（IP-MS）、蛋白-蛋白相互作用网络、共免疫沉淀（Co-IP）和免疫荧光法用于筛选与KLKB1相互作用的蛋白。结果：KLKB1通过与转录因子E3 （TFE3）相互作用促进VaD模型大鼠铁下垂。敲低KLKB1可降低TFE3表达水平，通过抑制BRaf/MEK/ERK信号级联抑制铁沉。在TFE3敲除后观察到一致的抗铁腐效应。结论：KLKB1-TFE3-BRaf/MEK/ERK信号轴是VaD中降低铁下垂的新靶点。

{"title":"The KLKB1–TFE3–BRAF/MEK/ERK axis regulates neuronal ferroptosis in vascular dementia","authors":"Yan Su , Lingqi Kong , Bowen Xue , Peng Shi , Sheng Cai , Yang Xu , Xianwen Chen , Hongdang Qu","doi":"10.1016/j.bbadis.2025.168119","DOIUrl":"10.1016/j.bbadis.2025.168119","url":null,"abstract":"<div><h3>Background</h3><div>Increasing evidence suggests that ferroptosis has significant implications for the pathogenesis of vascular dementia (VaD). Although KLKB1 exacerbates neurological damage in VaD by promoting ferroptosis, the exact mechanism remains unclear. The aim of this study is to elucidate the specific pathway through which KLKB1 mediates ferroptosis in VaD and to identify effective therapeutic strategies.</div></div><div><h3>Methods</h3><div>Rat models of VaD were constructed by bilateral common carotid artery occlusion (BCCAO). Behavioral impairment in VaD rats was assessed, along with pathological damage to hippocampal neurons. Transcriptome sequencing, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blotting, and quantitative real-time polymerase chain reaction (qPCR) were used to identify the downstream pathways through which KLKB1 regulates ferroptosis. Immunoprecipitation–mass spectrometry (IP–MS), protein–protein interaction networks, coimmunoprecipitation (Co-IP), and immunofluorescence assays were used to screen for proteins that interact with KLKB1.</div></div><div><h3>Results</h3><div>KLKB1 promotes ferroptosis in VaD model rats through its interaction with transcription factor E3 (TFE3). The knockdown of KLKB1 decreased TFE3 expression levels and suppressed ferroptosis through the inhibition of the BRaf/MEK/ERK signaling cascade. Consistent antiferroptotic effects were observed following TFE3 knockdown.</div></div><div><h3>Conclusion</h3><div>The KLKB1<strong>–</strong>TFE3<strong>–</strong>BRaf/MEK/ERK signaling axis represents a novel target for attenuating ferroptosis in VaD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 3","pages":"Article 168119"},"PeriodicalIF":4.2,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Exercise-induced irisin attenuates ferroptosis in polycystic ovary syndrome by modulating the NCOA4-FTH pathway 运动诱导的鸢尾素通过调节NCOA4-FTH通路减轻多囊卵巢综合征的铁下垂。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2025-11-12 DOI: 10.1016/j.bbadis.2025.168108

Yaling Zhang , Yi Zhang , Daojuan Wang , Yajing Weng , Shanmei Shen , Yanting Wen , Jianguo Ruan , Yong Wang

Objective

Hyperandrogenism is a central pathological feature of polycystic ovary syndrome (PCOS) that disrupts granulosa cell function. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, may contribute to ovarian injury. This study aimed to clarify the pathways of hyperandrogenic-induced granulosa cells ferroptosis, elucidating the molecular mechanism of exercise and its secretory factor, irisin, through the NCOA4-FTH pathway.

Methods

DHEA-induced PCOS model and in vitro granulosa cells were constructed to systematically evaluate the effects of exercise and irisin on ovarian function and ferroptosis. In vivo experiments included treadmill training in PCOS mice, assessment of estrous cycles, glucose/insulin tolerance, ovarian morphology, oxidative stress, ferroptosis, and NCOA4-FTH pathway proteins. In vitro, granulosa cells were treated with DHT and co-exposed to irisin or the ferroptosis inhibitor Ferrostatin-1 (Fer-1), with siRNA-mediated NCOA4 knockdown for functional verification.

Results

DHEA-induced PCOS mice exhibited disrupted estrous cycles, abnormal follicular morphology, glucose intolerance, insulin resistance, and ferroptosis activation, characterized by oxidative stress, Fe²⁺ overload, and dysregulated ferroptosis-related proteins. Fer-1 reversed DHT-induced GPX4 downregulation, suggesting ferroptosis involvement. Eight-week aerobic exercise improved metabolic parameters and ovarian morphology, suppressed ferroptosis by modulating NCOA4 and GPX4 expression, and alleviated oxidative stress. Mechanistically, exercise-induced irisin inhibited ferritinophagy and restored iron metabolism via the NCOA4-FTH pathway. NCOA4 knockdown further validated its central role in regulating ferritinophagy.

Conclusion

Hyperandrogenism triggers granulosa cells ferroptosis in PCOS, while exercise and irisin protect ovarian function by regulating the NCOA4–FTH pathway, suggesting a potential therapeutic target for PCOS.

目的：雄激素分泌过多是多囊卵巢综合征（PCOS）的中心病理特征，可破坏颗粒细胞功能。铁下垂是一种由脂质过氧化引起的铁依赖性细胞死亡形式，可能导致卵巢损伤。本研究旨在阐明高雄激素诱导的颗粒细胞铁下垂的途径，通过NCOA4-FTH途径阐明运动及其分泌因子鸢尾素的分子机制。方法：构建dhea诱导的PCOS模型和体外颗粒细胞，系统评价运动和鸢尾素对卵巢功能和铁下垂的影响。体内实验包括PCOS小鼠的跑步机训练、动情周期、葡萄糖/胰岛素耐量、卵巢形态、氧化应激、铁下垂和NCOA4-FTH途径蛋白的评估。在体外，用DHT处理颗粒细胞，并共同暴露于鸢尾素或铁凋亡抑制剂铁抑素-1 (ferl -1)，并通过sirna介导的NCOA4敲低进行功能验证。结果：dhea诱导的PCOS小鼠表现出发色周期中断、卵泡形态异常、葡萄糖耐受不良、胰岛素抵抗和铁凋亡激活，其特征是氧化应激、铁2+过载和铁凋亡相关蛋白失调。fer1逆转dht诱导的GPX4下调，提示铁下垂参与。8周有氧运动改善代谢参数和卵巢形态，通过调节NCOA4和GPX4表达抑制铁下垂，减轻氧化应激。机制上，运动诱导的鸢尾素通过NCOA4-FTH途径抑制铁蛋白自噬并恢复铁代谢。NCOA4敲低进一步证实了其在调节铁蛋白自噬中的核心作用。结论：高雄激素导致PCOS患者颗粒细胞铁下垂，而运动和鸢尾素通过调节NCOA4-FTH通路保护卵巢功能，提示PCOS的潜在治疗靶点。

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引用次数: 0