Biochimica et biophysica acta. Molecular basis of disease最新文献

Tumor-derived ITIH2 activates PI3KAKT pathway via THBS1 ubiquitination and promotes tumor angiogenesis in hepatocellular carcinoma 肿瘤来源的ITIH2通过THBS1泛素化激活PI3KAKT通路，促进肝癌肿瘤血管生成

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-29 DOI: 10.1016/j.bbadis.2026.168175

Zijian Liu , Jingsheng Yuan , Qiwen Zeng , Zhenru Wu , Jian Yang , Tao Lv

The heterogeneous tumor microenvironment (TME) plays a critical role in the initiation and progression of hepatocellular carcinoma (HCC). Within the TME, tumor vascular endothelial cells (ECs) are key stromal components that drive angiogenesis. However, the molecular mechanisms of interaction relationships between angiogenesis and tumor progression in HCC remain unclear. We performed clustering analysis on scRNA-seq data from two HCC patients (GSE166635) and identified eight distinct cell types using uniform manifold approximation and projection (UMAP). An eight-gene risk signature was established to predict patient prognosis. Using iterative least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression, we developed a risk scoring system and constructed a clinically applicable nomogram with TCGA HCC dataset as training cohort and ICGC HCC dataset as validation cohort. The predictive performance of the model was assessed and validated through calibration and decision curve analysis (DCA). Furthermore, we identified ITIH2 as a novel prognostic biomarker in HCC that may be associated with angiogenesis. Immunohistochemical (IHC) staining of clinical samples verified the prognostic value of ITIH2, which was also correlated with the levels of angiogenesis biomarkers, CD31 and CD34. Interestingly, functional experiments, including colony formation, CCK-8, and flow cytometry assays, revealed that ITIH2 overexpression did not alter tumor cell proliferation or apoptosis. Instead, ITIH2 enhanced the angiogenic capacity of ECs and promoted tumor progression in both in vitro and in vivo experiments. However, overexpression of THBS1 could reverse the function of ITIH2 on ECs and PI3K/AKT signaling pathway. Mechanistically, tumor-derived ITIH2 was associated with activation of the PI3K/AKT signaling pathway in ECs via a ubiquitination-dependent regulation of THBS1. The findings recapitulated that tumor-derived ITIH2 could promote HCC progression by enhancing the angiogenic ability of ECs by activating PI3K/AKT signaling pathway via THBS1 stability mediated by ubiquitination.

异质性肿瘤微环境（TME）在肝细胞癌（HCC）的发生和发展中起着至关重要的作用。在TME中，肿瘤血管内皮细胞（ECs）是驱动血管生成的关键基质成分。然而，HCC中血管生成与肿瘤进展相互作用的分子机制尚不清楚。我们对两名HCC患者（GSE166635）的scRNA-seq数据进行了聚类分析，并使用均匀流形近似和投影（UMAP）确定了8种不同的细胞类型。建立了一个8基因风险标记来预测患者预后。采用迭代最小绝对收缩和选择算子（LASSO）和多变量Cox回归，以TCGA HCC数据集为训练队列，ICGC HCC数据集为验证队列，建立了风险评分系统，并构建了临床适用的nomogram。通过标定和决策曲线分析（DCA）对模型的预测性能进行了评估和验证。此外，我们发现ITIH2是HCC中一种新的预后生物标志物，可能与血管生成有关。临床样品免疫组化（IHC）染色证实了ITIH2的预后价值，并且与血管生成生物标志物CD31和CD34的水平相关。有趣的是，包括集落形成、CCK-8和流式细胞术检测在内的功能实验显示，ITIH2过表达并未改变肿瘤细胞的增殖或凋亡。相反，在体外和体内实验中，ITIH2增强了ECs的血管生成能力，促进了肿瘤的进展。然而，过表达THBS1可以逆转ITIH2对ECs和PI3K/AKT信号通路的作用。机制上，肿瘤衍生的ITIH2通过泛素化依赖的THBS1调控与ECs中PI3K/AKT信号通路的激活相关。研究结果表明，肿瘤源性ITIH2可通过泛素化介导的THBS1稳定性激活PI3K/AKT信号通路，从而增强内皮细胞的血管生成能力，从而促进HCC的进展。

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引用次数: 0

Nano-curcumin mitigates muscle impairment in hypoxic hindlimb-unloaded mice 纳米姜黄素减轻缺氧后肢卸车小鼠的肌肉损伤

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-28 DOI: 10.1016/j.bbadis.2026.168178

Rizwan Qaisar , Saeed Ahmad Khan , Mutasem Rawas-Qalaji , Firdos Ahmad , Asima Karim

Background

Skeletal muscle atrophy due to hindlimb unloading (HU) is worsened under hypoxic conditions, mimicking clinical scenarios such as prolonged bed rest and chronic cardiopulmonary disease. Curcumin has therapeutic potential but suffers from poor bioavailability. This study evaluated the efficacy of curcumin encapsulated in zein-casein nanoparticles (Cur Z-CS NP) in mitigating muscle deterioration in HU mice under hypoxia.

Methods

Cur Z-CS NP were synthesized and characterized for physicochemical properties and drug release. Male C57BL/6 J mice were divided into normoxic and hypoxic groups, each further split into ground control and HU subgroups, and treated with placebo, free curcumin, or Cur Z-CS NP. Muscle function, histology, and gene expression were assessed in gastrocnemius muscles.

Results

Cur Z-CS NP exhibited favorable size, charge, and sustained curcumin release. HU and hypoxia significantly reduced body and muscle weights, as well as grip strength and fiber cross-sectional area (p < 0.05). Cur Z-CS NP treatment reversed these effects, increasing muscle mass and fiber size, and significantly improving grip strength. Myonuclear counts were preserved or elevated in treated HU mice, particularly under hypoxia. Cur Z-CS NP also reduced expression of caspase-1, spliced XBP-1, and MLKL, indicating suppression of apoptosis, ER stress, and necroptosis. Although MND size was decreased in HU hypoxic mice, Cur Z-CS NP partially restored it. Wire hanging time remained unaffected.

Conclusion

Cur Z-CS NP mitigates muscle atrophy and cellular stress in HU hypoxic mice, offering a promising therapeutic strategy for muscle wasting under conditions of disuse and hypoxia.

研究背景：在缺氧条件下，由后肢卸荷引起的骨骼肌萎缩会恶化，类似于长期卧床休息和慢性心肺疾病等临床情况。姜黄素具有治疗潜力，但生物利用度差。本研究评价了玉米蛋白酪蛋白纳米颗粒（Cur Z-CS NP）包被姜黄素对缺氧下HU小鼠肌肉退化的缓解作用。方法合成scurr Z-CS NP，并对其理化性质和药物释放特性进行表征。雄性C57BL/6 J小鼠分为常氧组和低氧组，再分为地面对照组和HU亚组，分别给予安慰剂、游离姜黄素或Cur Z-CS NP。对腓肠肌的肌肉功能、组织学和基因表达进行评估。结果cur Z-CS NP具有良好的大小、电荷和姜黄素持续释放特性。HU和缺氧显著降低了体重和肌肉质量，以及握力和纤维截面积（p < 0.05）。Cur Z-CS NP处理逆转了这些效应，增加了肌肉质量和纤维大小，并显著提高了握力。在治疗后的小鼠中，特别是在缺氧情况下，我的核计数保持不变或升高。Cur Z-CS NP还降低了caspase-1、剪接的XBP-1和MLKL的表达，表明抑制了细胞凋亡、内质网应激和坏死坏死。虽然HU缺氧小鼠的MND大小减小，但Cur Z-CS NP部分恢复了它。电线悬挂时间不受影响。结论cur Z-CS NP可减轻缺氧小鼠的肌肉萎缩和细胞应激，为治疗废用和缺氧条件下的肌肉萎缩提供了一种有前景的治疗策略。

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引用次数: 0

Thoracic aortic aneurysm and dissection: Similarities, differences and pharmacotherapy 胸主动脉瘤与夹层：异同及药物治疗

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-27 DOI: 10.1016/j.bbadis.2026.168174

Yan-Ni Hu , Mi Wang , Zheng Zhang

Aortic aneurysms and aortic dissections are major diseases affecting the thoracic aorta, with high morbidity and mortality. Thoracic aortic aneurysm (TAA) is characterized by bulge in the weakened aortic wall, which is usually asymptomatic and discovered incidentally during physical examination. Without timely intervention, approximately 50% of patients with TAA progress into aortic dissection. Thoracic aortic dissection (TAD) involves false lumen propagation from aortic intimal tear, with concomitant severe lancinating pain in the chest or back. TAA & TAD are highly similar in classification, predisposed sites, risk factors and causes, owing to the occurrence in the same segment of the aorta. Consequently, the collective term “thoracic aortic aneurysm and dissection (TAAD)” has been frequently used, and the definition of TAA & TAD is deemed interchangeable. However, TAA & TAD have essential differences in etiological causes and pathogenetic mechanisms. The mainstay treatment modalities of TAAD are open surgery or thoracic endovascular aortic repair, whereas targeted pharmacotherapies that can slow down, stop or reverse disease progression are lacking. This review summarizes the current knowledge in key aspects that aid in screening, surveilling, diagnosing and managing TAAD, and discusses similarities and differences between TAA and TAD, as well as pertinent pharmacotherapies.

主动脉瘤和主动脉夹层是影响胸主动脉的主要疾病，发病率和死亡率高。胸主动脉瘤（TAA）的特征是在虚弱的主动脉壁上出现凸起，通常无症状，在体检时偶然发现。如果不及时干预，大约50%的TAA患者会发展为主动脉夹层。胸主动脉夹层（TAD）包括主动脉内膜撕裂引起的假腔扩张，并伴有胸部或背部剧烈的刺痛。由于发生在主动脉同一节段，TAA和TAD在分类、易感部位、危险因素和病因上高度相似。因此，“胸主动脉瘤及夹层（TAAD）”这一统称被频繁使用，TAA &； TAD的定义被认为是可互换的。然而，TAA和TAD在病因和发病机制上存在本质差异。TAAD的主要治疗方式是开放手术或胸腔血管内主动脉修复，而目前缺乏能够减缓、停止或逆转疾病进展的靶向药物治疗。本文综述了目前在TAAD筛查、监测、诊断和管理的关键方面的知识，并讨论了TAA与TAD的异同，以及相关的药物治疗方法。

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引用次数: 0

ATP6V0d2 alleviates acute liver injury via promoting hepatocyte autophagy ATP6V0d2通过促进肝细胞自噬减轻急性肝损伤

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-27 DOI: 10.1016/j.bbadis.2026.168170

Mengxia Zhang , Zhemin Shi , Yi Yang , Yue Huang , Kefei Guo , Yuying Sun , Jianan Gao , Jiajun Wang , Yanjun Li , Wei Hong , Tao Han , Kun Zhang

Liver injury is the pathological basis of various liver diseases, and severe acute liver injury can progress to acute liver failure with a high mortality. Although continuous progress has been made over the past few decades, the molecular mechanism underlying the progress of acute liver injury is still unclear. ATP6V0d2, a subunit of the vacuolar ATPase (V-ATPase) complex, is implicated in organelle acidification and intracellular degradation processes. In this study, three liver injury datasets were analyzed to screen the differentially expressed genes (DEGs) and identify Atp6v0d2, which was initially downregulated, and then upregulated to slightly higher than normal levels in both hepatocytes (HCs) and liver tissues in carbon tetrachloride (CCl₄)-induced acute liver injury, with the most significant downregulation observed 24 h after CCl₄ injection. Moreover, hepatocyte-specific overexpression of ATP6V0d2 alleviated CCl₄, concanavalin A (ConA) and acetaminophen (APAP)-induced acute liver injury by promoting hepatocyte autophagy, while silencing ATP6V0d2 inhibited hepatocyte autophagy and aggravated liver injury in vivo. In addition, consistent with the results of gene enrichment analysis, in vitro data demonstrated that ATP6V0d2 promoted hepatocyte autophagy mainly via facilitating the formation of autophagosomes. In conclusion, our results demonstrated that ATP6V0d2 played a protective role in acute liver injury by facilitating hepatocyte autophagy, which may provide a theoretical basis for the treatment and prognosis of acute liver injury.

肝损伤是各种肝脏疾病的病理基础，严重的急性肝损伤可发展为急性肝衰竭，死亡率高。虽然在过去的几十年里取得了不断的进展，但急性肝损伤进展的分子机制仍不清楚。ATP6V0d2是液泡atp酶（v - atp酶）复合物的一个亚基，参与细胞器酸化和细胞内降解过程。本研究通过对3组肝损伤数据进行分析，筛选差异表达基因（DEGs），鉴定出Atp6v0d2，在四氯化碳（CCl4）诱导的急性肝损伤中，Atp6v0d2在肝细胞（hc）和肝组织中均呈先下调后上调至略高于正常水平，且在注射CCl4 24 h后下调最为显著。此外，肝细胞特异性过表达ATP6V0d2通过促进肝细胞自噬，减轻CCl4、豆豆蛋白A （ConA）和对乙酰氨基酚（APAP）诱导的急性肝损伤，而在体内沉默ATP6V0d2抑制肝细胞自噬，加重肝损伤。此外，与基因富集分析结果一致，体外实验数据表明，ATP6V0d2主要通过促进自噬体的形成来促进肝细胞自噬。综上所述，我们的研究结果表明，ATP6V0d2通过促进肝细胞自噬在急性肝损伤中发挥保护作用，这可能为急性肝损伤的治疗和预后提供理论依据。

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引用次数: 0

Circ_0075691 regulates lipid metabolism in granulosa cells by interacting with EIF4A3 to promote PTGS2 mRNA stability Circ_0075691通过与EIF4A3相互作用促进PTGS2 mRNA的稳定性，调控颗粒细胞的脂质代谢

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-26 DOI: 10.1016/j.bbadis.2026.168173

Pengyu Huang , Jianshu Cai , Gangxin Chen , Huiling Xu , Suzhu Chen , Haiyan Li , Yun Fu , Beihong Zheng , Zhengmian Zhang

Background

Circular RNAs (circRNAs) are implicated in polycystic ovary syndrome (PCOS), yet their roles in granulosa cell dysfunction remain unclear. This study explores the mechanistic role of circ_0075691 in PCOS-associated metabolic dysregulation.

Methods

The circular structure of circ_0075691 was confirmed through gel electrophoresis and RNase R resistance assays. Its expression levels and subcellular localization were assessed using RT-PCR and fluorescence in situ hybridization (FISH). Subsequent to the overexpression of circ_0075691, the cell function assays were conducted, including CCK-8, colony formation, flow cytometry, and analyses of oxidative stress and lipid metabolism-related indicators. Bioinformatics analyses were employed to predict RNA-binding proteins (RBPs) that potentially interact with circ_0075691, and these interactions were validated using RNA immunoprecipitation (RIP) and RNA pulldown assays.

Results

Circ_0075691 was verified to possess a circular structure and was predominantly localized in the nucleus. Its expression was significantly elevated in both follicular fluid (FF) and granulosa cells from PCOS patients compared to normal controls. In vitro experiments demonstrated that overexpression of circ_0075691 led to reduced cell viability and proliferation, decreased oxygen consumption rate (OCR), and increased apoptosis, oxidative stress, and lipid accumulation. Mechanistically, circ_0075691 was found to interact with and stabilize the EIF4A3 protein, thereby enhancing the stability of PTGS2 mRNA. Silencing PTGS2 mitigated the metabolic and apoptotic abnormalities induced by circ_0075691.

Conclusion

This study revealed that circ_0075691 played a crucial role in PCOS-related granulosa cell functions and lipid metabolism. The circ_0075691/EIF4A3/PTGS2 axis provided new insights into the molecular mechanism of PCOS and potential therapeutic targets.

环状rna （circRNAs）与多囊卵巢综合征（PCOS）有关，但其在颗粒细胞功能障碍中的作用尚不清楚。本研究探讨了circ_0075691在pcos相关代谢失调中的机制作用。方法通过凝胶电泳和RNase R耐药试验证实circ_0075691为圆形结构。采用RT-PCR和荧光原位杂交（FISH）技术检测其表达水平和亚细胞定位。过表达circ_0075691后，进行细胞功能检测，包括CCK-8、集落形成、流式细胞术、氧化应激和脂质代谢相关指标分析。利用生物信息学分析预测RNA结合蛋白（rbp）可能与circ_0075691相互作用，并利用RNA免疫沉淀（RIP）和RNA拉下试验验证这些相互作用。结果证实scirc_0075691具有圆形结构，主要定位于细胞核。与正常对照相比，PCOS患者的卵泡液（FF）和颗粒细胞中其表达均显著升高。体外实验表明，circ_0075691过表达导致细胞活力和增殖降低，氧消耗率（OCR）降低，细胞凋亡、氧化应激和脂质积累增加。机制上，circ_0075691与EIF4A3蛋白相互作用并稳定EIF4A3蛋白，从而增强PTGS2 mRNA的稳定性。沉默PTGS2可减轻circ_0075691诱导的代谢和凋亡异常。结论circ_0075691在pcos相关颗粒细胞功能和脂质代谢中发挥重要作用。circ_0075691/EIF4A3/PTGS2轴为PCOS的分子机制和潜在的治疗靶点提供了新的见解。

{"title":"Circ_0075691 regulates lipid metabolism in granulosa cells by interacting with EIF4A3 to promote PTGS2 mRNA stability","authors":"Pengyu Huang , Jianshu Cai , Gangxin Chen , Huiling Xu , Suzhu Chen , Haiyan Li , Yun Fu , Beihong Zheng , Zhengmian Zhang","doi":"10.1016/j.bbadis.2026.168173","DOIUrl":"10.1016/j.bbadis.2026.168173","url":null,"abstract":"<div><h3>Background</h3><div>Circular RNAs (circRNAs) are implicated in polycystic ovary syndrome (PCOS), yet their roles in granulosa cell dysfunction remain unclear. This study explores the mechanistic role of circ_0075691 in PCOS-associated metabolic dysregulation.</div></div><div><h3>Methods</h3><div>The circular structure of circ_0075691 was confirmed through gel electrophoresis and RNase R resistance assays. Its expression levels and subcellular localization were assessed using RT-PCR and fluorescence in situ hybridization (FISH). Subsequent to the overexpression of circ_0075691, the cell function assays were conducted, including CCK-8, colony formation, flow cytometry, and analyses of oxidative stress and lipid metabolism-related indicators. Bioinformatics analyses were employed to predict RNA-binding proteins (RBPs) that potentially interact with circ_0075691, and these interactions were validated using RNA immunoprecipitation (RIP) and RNA pulldown assays.</div></div><div><h3>Results</h3><div>Circ_0075691 was verified to possess a circular structure and was predominantly localized in the nucleus. Its expression was significantly elevated in both follicular fluid (FF) and granulosa cells from PCOS patients compared to normal controls. In vitro experiments demonstrated that overexpression of circ_0075691 led to reduced cell viability and proliferation, decreased oxygen consumption rate (OCR), and increased apoptosis, oxidative stress, and lipid accumulation. Mechanistically, circ_0075691 was found to interact with and stabilize the EIF4A3 protein, thereby enhancing the stability of PTGS2 mRNA. Silencing PTGS2 mitigated the metabolic and apoptotic abnormalities induced by circ_0075691.</div></div><div><h3>Conclusion</h3><div>This study revealed that circ_0075691 played a crucial role in PCOS-related granulosa cell functions and lipid metabolism. The circ_0075691/EIF4A3/PTGS2 axis provided new insights into the molecular mechanism of PCOS and potential therapeutic targets.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1872 4","pages":"Article 168173"},"PeriodicalIF":4.2,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146074774","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

Mitigating loss of lean muscle in GLP-1 and dual GLP-1/GIP agonists: Pipeline opportunities and limitations 减轻GLP-1和双GLP-1/GIP激动剂的瘦肌肉损失：管道的机会和限制。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-24 DOI: 10.1016/j.bbadis.2026.168172

Justin Hierholzer , Harrison Benson , Heba A. Ewida , Mahmoud Salama Ahmed

Glucagon-like peptide-1 (GLP-1) receptor and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists drive significant transformation in the landscape for type 2 diabetes and obesity management, yet 15–40% of weight loss in trials like STEP and SURMOUNT stems from lean muscle mass. This catabolic loss impairs glucose disposal, muscle strength, and physical function; elevating risks for the loss of force generating capacity in the skeletal muscles leading to sarcopenia, particularly in elderly patients. Unfortunately, current FDA guidelines emphasize total weight reduction over body composition, featuring an unmet critical need for elucidating strategies to preserve loss of lean muscle. This review will feature the emerging therapeutics to mitigate loss of lean muscle, including selective androgen receptor modulators, myostatin-targeting TGF-β inhibitors, and gene-silencing siRNA therapies. Despite promising preclinical and early clinical data, limitations persist, including reliance on parenteral biologics, limited mechanistic diversity, short trial durations, and sparse functional outcome data. Future research must prioritize precise muscle assessments, body composition, long-term trials, and accessible interventions integrating pharmacotherapy. These advances could redefine weight loss paradigms, ensuring therapeutic efficacy aligns with optimal body composition and patient outcomes.

胰高血糖素样肽-1 （GLP-1）受体和双GLP-1/葡萄糖依赖性胰岛素多肽（GIP）激动剂推动了2型糖尿病和肥胖管理领域的重大转变，但在STEP和SURMOUNT等试验中，15-40%的体重减轻源于瘦肌肉量。这种分解代谢损失损害葡萄糖处理、肌肉力量和身体功能；增加骨骼肌力量产生能力丧失的风险，导致肌肉减少症，特别是老年患者。不幸的是，目前FDA的指导方针强调总体体重的减少，而不是身体成分的减少，这对阐明保持瘦肌肉损失的策略具有未满足的关键需求。本综述将重点介绍减轻瘦肌肉损失的新疗法，包括选择性雄激素受体调节剂、靶向肌肉生成抑制素TGF-β抑制剂和基因沉默siRNA疗法。尽管临床前和早期临床数据很有希望，但局限性仍然存在，包括对肠外生物制剂的依赖，有限的机制多样性，试验持续时间短，功能结果数据稀疏。未来的研究必须优先考虑精确的肌肉评估、身体成分、长期试验和可获得的药物治疗干预措施。这些进步可以重新定义减肥范例，确保治疗效果与最佳身体成分和患者结果相一致。

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引用次数: 0

Goosecoid promotes hepatic stellate cell epithelial-mesenchymal transition via transcriptional activation of serum- and glucocorticoid-induced protein kinase 1 in liver fibrosis 鹅样蛋白通过激活血清和糖皮质激素诱导的蛋白激酶1在肝纤维化中促进肝星状细胞上皮-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 : 2026-01-24 DOI: 10.1016/j.bbadis.2026.168169

Yongjuan Wang , Xiaoli Xie , Jiajun Tian , Xiaoyu Jiang , Huiqing Jiang

Background

Goosecoid (GSC) is a transcription factor implicated in epithelial-mesenchymal transition (EMT) during embryogenesis and cancer, but its function in organ fibrosis remains poorly understood. This study investigates the role and mechanistic targets of GSC in hepatic stellate cell (HSC) EMT during liver fibrogenesis.

Methods

We analyzed GSC and EMT marker expression in primary HSCs isolated from murine liver fibrosis models induced by carbon tetrachloride (CCl₄) or bile duct ligation (BDL), and in TGF-β-stimulated LX-2 cells. The functional role of GSC was validated via in vitro and in vivo GSC knockdown, while chromatin immunoprecipitation sequencing (ChIP-seq) combined with experimental verification was used to identify its target genes and regulatory mechanisms.

Results

GSC expression was significantly upregulated in activated HSCs from fibrotic mouse models and TGF-β-induced LX-2 cells, which was closely associated with enhanced EMT (downregulation of epithelial markers, upregulation of mesenchymal markers). Functional assays confirmed that GSC knockdown suppressed HSC EMT in vitro and ameliorated liver fibrosis in vivo via AAV-mediated HSC-specific GSC silencing. Mechanistically, we found that GSC undergoes increased nuclear translocation during HSC activation. ChIP-seq analysis identified Serum- and glucocorticoid-induced protein kinase 1 (SGK1) as a direct transcriptional target of GSC. Further validation revealed that SGK1, in turn, promotes HSC EMT by activating the NF-κB signaling pathway.

Conclusion

This study uncovers a novel mechanism by which GSC promotes HSC EMT and liver fibrosis through direct transcriptional activation of SGK1, followed by downstream NF-κB pathway activation.

Summary

GSC is markedly upregulated in activated HSCs from murine fibrosis models (CCl₄/BDL) and during TGF-β-induced EMT. HSC-specific GSC knockdown attenuated liver fibrosis progression. Mechanistically, GSC translocates to the nucleus where it binds the SGK1 promoter to enhance transcription, subsequently driving HSC EMT and promoting fibrogenesis through the NF-κB signaling pathway.

goosecoid （GSC）是一种涉及胚胎发生和癌症期间上皮-间充质转化（EMT）的转录因子，但其在器官纤维化中的功能尚不清楚。本研究探讨了GSC在肝纤维化过程中肝星状细胞（HSC） EMT中的作用及其机制靶点。方法分析四氯化碳（CCl₄）或胆管结扎（BDL）诱导的小鼠肝纤维化模型中分离的原代hsc和TGF-β刺激的LX-2细胞中GSC和EMT标志物的表达。通过体外和体内GSC敲低验证了GSC的功能作用，并利用染色质免疫沉淀测序（ChIP-seq）结合实验验证鉴定了其靶基因和调控机制。结果在纤维化小鼠模型和TGF-β诱导的LX-2细胞活化的hsc中，gsc表达显著上调，这与EMT（上皮标记下调，间充质标记上调）增强密切相关。功能分析证实，GSC敲除在体外抑制HSC EMT，并通过aav介导的HSC特异性GSC沉默在体内改善肝纤维化。在机制上，我们发现在HSC激活过程中，GSC经历了核易位的增加。ChIP-seq分析发现血清和糖皮质激素诱导的蛋白激酶1 （SGK1）是GSC的直接转录靶点。进一步的验证表明，SGK1反过来通过激活NF-κB信号通路促进HSC EMT。结论本研究揭示了GSC通过直接转录激活SGK1，进而激活下游NF-κB通路促进HSC EMT和肝纤维化的新机制。小鼠纤维化模型（CCl₄/BDL）和TGF-β诱导的EMT中活化的hsc中gsc明显上调。hsc特异性GSC敲除可减轻肝纤维化进展。在机制上，GSC易位到细胞核，在那里它结合SGK1启动子来增强转录，随后通过NF-κB信号通路驱动HSC EMT并促进纤维形成。

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引用次数: 0

Placental aberrant inflammation and spatial-specific lipid metabolism contribute to hypertensive disorder of pregnancy susceptibility in preeclampsia offspring 胎盘异常炎症和空间特异性脂质代谢有助于子痫前期子代妊娠易感性高血压障碍。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-19 DOI: 10.1016/j.bbadis.2026.168168

Pei-ran Hu , Jing-hui Xu , Yan Shi , Ying Zhu , Gao-chen Zhang , Jie-ru Yang , Yue Xu , Ming-hao Li , Xian-hua Lin , Yu Zhang , He-feng Huang

Epidemiological studies have demonstrated that daughters of preeclamptic mothers have an increased risk of hypertensive disorders of pregnancy (HDP), but the underlying mechanisms remain unclear. To investigate the molecular changes underlying this HDP intergenerational transmission, we established an L-NAME-induced PE model in pregnant mice (F0) and examined female offspring (F1) during their pregnancies. F1 females developed gestational hypertension in late pregnancy, accompanied by enlarged placental labyrinthine areas and elevated VGFR1 expression, despite normal circulating sFlt1 levels. Across gestation, F2 placentas exhibited sustained impairment of apolipoprotein-mediated lipid transport beginning at mid-gestation, while inflammatory and HIF1α pathways were mainly activated at late gestation. Spatial transcriptomic data further showed that apolipoproteins were predominantly localized to yolk sac regions, whereas inflammatory factors exhibited widespread distribution. Importantly, F1 maternal lipid profiles remained normal before conception but manifested elevated serum triglyceride levels during pregnancy, concurrent with placental lipid accumulation. This pregnancy-specific dyslipidemia suggests that placental lipid metabolism dysfunction may contribute to maternal lipid dysregulation. Clinical validation in 28,117 women further confirmed that elevated mid-gestation triglyceride levels were strongly associated with HDP risk, consistent with the dyslipidemia observed in our mouse model. Together, these findings demonstrate that pregnancy-specific lipid dysregulation represents a conserved mechanism linking placental dysfunction to HDP susceptibility. Our study provides mechanistic insights into the intergenerational transmission of PE and identifies mid-gestation maternal lipid profiles as potential predictive biomarkers, offering a basis for early risk assessment and future therapeutic targeting.

流行病学研究表明，先兆子痫母亲的女儿患妊娠高血压疾病（HDP）的风险增加，但其潜在机制尚不清楚。为了研究HDP代际传递背后的分子变化，我们在怀孕小鼠（F0）中建立了l - name诱导的PE模型，并对怀孕期间的雌性后代（F1）进行了检测。F1女性在妊娠后期出现妊娠高血压，伴随着胎盘迷路面积增大和VGFR1表达升高，尽管循环sFlt1水平正常。在整个妊娠期间，F2胎盘从妊娠中期开始表现出载脂蛋白介导的脂质转运持续受损，而炎症和HIF1α途径主要在妊娠后期被激活。空间转录组学数据进一步表明，载脂蛋白主要集中在卵黄囊区域，而炎症因子则分布广泛。重要的是，F1孕妇的血脂在受孕前保持正常，但在怀孕期间表现出血清甘油三酯水平升高，同时伴有胎盘脂质积累。这种妊娠期特异性血脂异常提示胎盘脂质代谢功能障碍可能导致母体脂质失调。28,117名妇女的临床验证进一步证实妊娠中期甘油三酯水平升高与HDP风险密切相关，与我们在小鼠模型中观察到的血脂异常一致。总之，这些发现表明，妊娠特异性脂质失调代表了一种将胎盘功能障碍与HDP易感性联系起来的保守机制。我们的研究为PE的代际传播提供了机制见解，并确定了妊娠中期母亲脂质谱作为潜在的预测性生物标志物，为早期风险评估和未来的治疗靶向提供了基础。

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引用次数: 0

Berbamine attenuates acetaminophen-induced liver injury by engaging GCLC and enhancing ferroptosis-regulatory antioxidant pathways 小檗碱通过参与GCLC和增强铁凋亡调节抗氧化途径减轻对乙酰氨基酚诱导的肝损伤

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-14 DOI: 10.1016/j.bbadis.2026.168154

Mengli Tao , Jiayi Shi , Yingying Zhang , Yigang Zheng , Yufen Zhao , Huabin Ma , Long Li

Objective

Acetaminophen (APAP)-induced liver injury (ALI), the major cause of acute drug-induced hepatotoxicity, lacks effective therapies. Berbamine (BBM), a bisbenzylisoquinoline alkaloid derived from the genus Berberis, exhibits diverse pharmacological properties but its efficacy against ALI and involvement in ferroptosis remains unexplored. This study aims to investigate the hepatoprotective effects and mechanisms of BBM against ALI and ferroptosis.

Methods

The in vivo model of ALI and the in vitro ferroptosis models were established using APAP and RSL3, respectively. Models received BBM or Ferrostatin-1 (Fer-1) treatment. The direct target of BBM was identified through molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) assays.

Results

In vivo, BBM pretreatment dose-dependently alleviated APAP-induced hepatic damage, inflammation, and ferroptosis markers, including lipid peroxidation, GSH depletion, and PTGS2 upregulation, while upregulating GPX4. Meanwhile, the hepatoprotective effects of BBM against ALI matched Fer-1, confirming ferroptosis as an ALI driver. In vitro, BBM inhibited RSL3-induced ferroptosis, reducing ROS, lipid peroxidation, and mitochondrial dysfunction. These effects were mediated by NRF2/GCLC/GPX4 axis activation and FSP1 upregulation. Crucially, BBM directly bound GCLC confirmed by Molecular docking, CETSA, and DARTS.

Conclusion

BBM protects against ALI by mitigating ferroptosis, oxidative stress, and inflammation, in part through direct modulation of GCLC and coordinated activation of the NRF2/GCLC/GPX4 axis together with FSP1. These findings provide pharmacological evidence supporting the potential of BBM as a promising therapeutic candidate for ALI.

目的对乙酰氨基酚（APAP）致肝损伤（ALI）是急性药物性肝毒性的主要原因，缺乏有效的治疗方法。小檗碱（BBM）是一种从小檗属植物中提取的双苄基异喹啉类生物碱，具有多种药理特性，但其对ALI的疗效和对铁下垂的影响尚不清楚。本研究旨在探讨BBM对ALI和铁下沉的肝保护作用及其机制。方法采用APAP和RSL3分别建立ALI体内模型和体外铁下垂模型。模型接受BBM或铁他汀-1 （ferr -1）治疗。通过分子对接、细胞热移测定（CETSA）和药物亲和反应靶稳定性（DARTS）测定确定BBM的直接靶点。结果在体内，BBM预处理剂量依赖性地减轻了apap诱导的肝损伤、炎症和铁死亡标志物，包括脂质过氧化、GSH耗竭和PTGS2上调，同时上调GPX4。同时，BBM对ALI的肝保护作用与fe -1相匹配，证实了铁下沉是ALI的驱动因素。在体外，BBM抑制rsl3诱导的铁下垂，减少ROS、脂质过氧化和线粒体功能障碍。这些作用是由NRF2/GCLC/GPX4轴激活和FSP1上调介导的。至关重要的是，BBM直接结合了经分子对接、CETSA和dart证实的GCLC。结论bbm通过直接调节GCLC和NRF2/GCLC/GPX4轴与FSP1的协同激活，减轻铁下沉、氧化应激和炎症，从而对ALI具有保护作用。这些发现提供了药理学证据，支持BBM作为ALI的有希望的治疗候选药物的潜力。

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引用次数: 0

SIRT5 promotes vascular regeneration in peripheral muscle ischemia by regulating malonylation and glycolysis SIRT5通过调节丙二醛化和糖酵解促进外周肌肉缺血血管再生。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-01-12 DOI: 10.1016/j.bbadis.2026.168163

Kanghui Chen , Hang Chen , Peng Wang , Yueyi Pan , Heng Yang , Aijun Sun , Junbo Ge , Xueying Chen , Lei Xu , Xiaolei Sun

Peripheral artery disease (PAD) is a prominent contributor to the global prevalence and mortality of cardiovascular diseases, yet the therapeutic strategies remain limited and urgently to explore the new methods of promoting vascular regeneration. Metabolism involves numerous aspects of angiogenesis, including the energetics, proliferation, signal transduction and gene expression of endothelial cells (ECs). Sirtuin (SIRT) family play an important role in regulating numerous metabolic processes due to its protein modification activity. Herein, the effect of SIRTs on regulating muscle vascular regeneration of PAD patients was demonstrated. We reanalyzed the SIRTs family by using the reported data of single-nuclei atlas of human PAD limb muscle and found that SIRT5 expression in ECs was significantly downregulated. Then the dynamic changes of SIRTs in ischemic hindlimb of mice and hypoxia-induced HUVECs were observed, among which, SIRT5 showed the most sensitive and significant change in responding to ischemia. Deletion of SIRT5 inhibited the blood flow perfusion recovery and consequently aggravated ischemic hindlimb injury in mice. SIRT5 knock down in vitro inhibited the proliferation, migration and angiogenesis of HUVECs both under normoxia and hypoxia. The mechanism was involved in significantly decreased expression of glycolytic enzymes and increased malonylation of proteins, especially GAPDH, in HUVECs with SIRT5 knock down. In conclusion, SIRT5 controlled the vascular regeneration capacity of lower limb muscles by regulating glycolysis and malonylation modification. Regulating SIRT5 activity might be novel therapeutic target for PAD patients.

外周动脉疾病（PAD）是全球心血管疾病患病率和死亡率的重要因素，但治疗策略仍然有限，迫切需要探索促进血管再生的新方法。代谢涉及血管生成的许多方面，包括内皮细胞（ECs）的能量学、增殖、信号转导和基因表达。Sirtuin （SIRT）家族由于其蛋白修饰活性在调节多种代谢过程中发挥重要作用。本研究证明了SIRTs对PAD患者肌肉血管再生的调节作用。我们利用已报道的人类PAD肢体肌肉单核图谱数据重新分析了SIRT5家族，发现SIRT5在ECs中的表达显著下调。然后观察小鼠后肢缺血和缺氧诱导HUVECs中SIRTs的动态变化，其中SIRT5在响应缺血时表现出最敏感、最显著的变化。SIRT5的缺失抑制了血流灌注恢复，从而加重了小鼠后肢缺血性损伤。SIRT5基因敲低在常氧和缺氧条件下均能抑制HUVECs的增殖、迁移和血管生成。其机制涉及SIRT5敲低的HUVECs中糖酵解酶的表达显著降低，丙二醛化蛋白（尤其是GAPDH）的表达增加。综上所述，SIRT5通过调节糖酵解和丙二醛化修饰来控制下肢肌肉的血管再生能力。调节SIRT5活性可能是PAD患者新的治疗靶点。

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引用次数: 0