Biochimica et biophysica acta. Molecular basis of disease最新文献_第6页

Type 5 diabetes: A comprehensive review to understand the basis of diabetes of poverty 5型糖尿病：了解贫困糖尿病基础的综合综述。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-26 DOI: 10.1016/j.bbadis.2025.168147

Jalal Taneera , Rania Saeed , Eglal Mahgoub , Zamzam Farhan , Abdalla Alobeidli , Mariyam Shoukat , Nael Shaat

Malnutrition-Related Diabetes Mellitus (MRDM) is a subtype of diabetes associated with chronic malnutrition, primarily observed in low- and middle-income countries (LMICs) and impoverished populations. The disease is characterized by onset in young, lean patients with a history of chronic undernutrition, insulin deficiency, persistent insulin sensitivity, and resistance to ketosis. MRDM was recognized by the World Health Organization (WHO) in 1985, then removed from classification in 1999 due to a lack of evidence. Emerging evidence has revealed a unique pathophysiology, prompting the International Diabetes Federation (IDF) to officially recognize MRDM as “Type 5 Diabetes” (T5D). This review synthesizes the evidence that validates T5D as a distinct endotype, which is mechanistically different from other diabetes types. It delineates the epidemiological patterns of T5D and focuses on the pathophysiological “blueprint” of the malnourished pancreas. It also integrates evidence showing how early-life nutritional deprivation, including protein and micronutrient deficiencies, programmatically reduces β-cell mass and function through mechanisms such as mitochondrial dysfunction, endoplasmic reticulum stress, oxidative damage, and persistent epigenetic modifications. Current management strategies and the distinct profile of long-term complications are highlighted. Finally, the review outlines pressing future directions, arguing that the formal recognition of T5D provides an opportunity for coordinated research and policy initiatives that address the root causes and consequences of this diabetes of poverty.

营养不良相关性糖尿病（MRDM）是一种与慢性营养不良相关的糖尿病亚型，主要见于低收入和中等收入国家（LMICs）和贫困人群。该病的特点是发病于年轻、瘦弱、有慢性营养不良、胰岛素缺乏、持续胰岛素敏感和酮症抵抗史的患者。MRDM于1985年被世界卫生组织（WHO）承认，但由于缺乏证据，于1999年从分类中删除。新出现的证据揭示了一种独特的病理生理学，促使国际糖尿病联合会（IDF）正式承认MRDM为“5型糖尿病”（T5D）。这篇综述综合了证实T5D是一种独特的内型的证据，它在机制上不同于其他类型的糖尿病。它描述了T5D的流行病学模式，并着重于营养不良胰腺的病理生理“蓝图”。它还整合了早期营养剥夺（包括蛋白质和微量营养素缺乏）如何通过线粒体功能障碍、内质网应激、氧化损伤和持续表观遗传修饰等机制程序性地减少β细胞质量和功能的证据。当前的管理策略和长期并发症的独特轮廓突出。最后，该综述概述了紧迫的未来方向，认为正式承认T5D为协调研究和政策举措提供了机会，以解决这种贫困糖尿病的根本原因和后果。

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引用次数: 0

Ubiquitin-specific peptidase 40 promotes cellular proliferation and inhibits apoptosis through deubiquitination-mediated stabilization of c-MYC in acute myeloid leukemia 在急性髓性白血病中，泛素特异性肽酶40通过去泛素化介导的c-MYC稳定促进细胞增殖和抑制凋亡。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-15 DOI: 10.1016/j.bbadis.2025.168138

Wen Fu , Qiaoliang Wu , Yanru Yao , Yingsen Sun , Huafang Wang , Jing Jie , Xiaoyan Zheng , Lina Wang , Xiaoge Hu , Xiangmin Tong , Qiuran Xu

Background

Ubiquitin-specific peptidase 40(USP40), a member of the deubiquitinase family, regulates numerous cellular processes. Recent studies have increasingly highlighted the involvement of USP40 in cancer development. However, the precise mechanism through which USP40 influences acute myeloid leukemia (AML) progression remains poorly understood.

Methods

The expression levels of USP40 in AML tissues and cell lines were examined using Gene Expression Profiling Interactive Analysis, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting (WB). The Kaplan-Meier plotter was used to evaluate the association between USP40 expression and prognosis in patients with AML. Cell Counting Kit-8, 5-ethynyl-2′-deoxyuridine incorporation, apoptosis assays, and subcutaneous tumor models in nude mice were applied to determine the effects of USP40 expression on AML cell proliferation and apoptosis in vitro and in vivo. WB, RT-qPCR, immunofluorescence assay, co-immunoprecipitation assay, and cycloheximide chase assay were conducted to explore the relationship between USP40 and c-MYC. Rescue experiments were further performed to assess the functional contribution of USP40-c-MYC axis to AML progression.

Results

USP40 was overexpressed in AML tissues and cell lines compared to normal controls and correlated with poor prognosis. USP40 accelerated AML progression by promoting proliferation and inhibiting apoptosis. Mechanistically, USP40 deubiquitinated c-MYC by selectively removing K48-linked polyubiquitin chains, thereby preventing its degradation via the ubiquitin–proteasome pathway.

Conclusion

USP40 accelerated AML progression by deubiquitinating c-MYC, highlighting the USP40-c-MYC axis as a potential therapeutic target for AML treatment.

背景：泛素特异性肽酶40（USP40）是去泛素酶家族的一员，调节许多细胞过程。最近的研究越来越强调USP40在癌症发展中的作用。然而，USP40影响急性髓性白血病（AML）进展的确切机制仍然知之甚少。方法：采用基因表达谱交互分析、逆转录定量聚合酶链反应（RT-qPCR）和western blotting （WB）检测AML组织和细胞系中USP40的表达水平。Kaplan-Meier绘图仪用于评估AML患者USP40表达与预后之间的关系。采用细胞计数试剂盒- 8,5 -乙基-2'-脱氧尿苷掺入、细胞凋亡实验和裸鼠皮下肿瘤模型研究USP40表达对体外和体内AML细胞增殖和凋亡的影响。采用WB、RT-qPCR、免疫荧光法、共免疫沉淀法、环己亚胺追踪法等方法探讨USP40与c-MYC的关系。我们进一步进行了拯救实验，以评估USP40-c-MYC轴在AML进展中的功能贡献。结果：与正常对照相比，USP40在AML组织和细胞系中过表达，且与不良预后相关。USP40通过促进增殖和抑制细胞凋亡加速AML进展。在机制上，USP40通过选择性去除k48连接的多泛素链来去泛素化c-MYC，从而阻止其通过泛素-蛋白酶体途径降解。结论：USP40通过去泛素化c-MYC加速AML进展，凸显了USP40-c-MYC轴作为AML治疗的潜在治疗靶点。

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引用次数: 0

ATOX1-driven ECM degradation and vascular smooth muscle cell apoptosis accelerate aortic dissection progression atox1驱动的ECM降解和血管平滑肌细胞凋亡加速了主动脉夹层的进展。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-16 DOI: 10.1016/j.bbadis.2025.168134

Yuling Xie , Xinfan Lin , Xu Han , Xingfeng Chen , Qingsong Wu , Debin Jiang , Linfeng Xie

Background

The development of aortic dissection (AD) is closely associated with extracellular matrix degradation and the apoptosis of vascular smooth muscle cells (VSMCs). Antioxidant-1 (ATOX1), a copper-binding protein, the precise mechanisms by which it contributes to extracellular matrix (ECM) degradation, VSMC apoptosis, and the onset of AD remain to be further elucidated.

Methods and results

Through high-throughput sequencing, we identified a significant increase in the expression of ATOX1 in patients with AD. Further validation using tissue staining, RT-PCR and Western blot revealed that ATOX1 expression was elevated in AD patients, AD mouse models, and in vitro human aortic vascular smooth muscle cells (HAVSMCs) induced by Angiotensin II (AngII). In vitro experiments showed that silencing ATOX1 or pharmacologically inhibiting ATOX1 with DC_AC50 significantly reduced copper ion expression and the secretion of matrix metalloproteinases (MMPs), while alleviating cell apoptosis in HAVSMCs. Targeted knockdown of ATOX1 in smooth muscle cells using adeno-associated virus vector 9 (AAV9) or pharmacological inhibition of ATOX1 effectively slowed the progression of AD in a β-aminopropionitrile (BAPN)-induced mouse model. Additionally, ATOX1 expression is directly regulated by miR-133b, which was found to be significantly downregulated in the serum and aortic tissues of AD patients, exhibiting an inverse correlation with ATOX1 upregulation in AD. MiR-133b mimic successfully reversed the effects of ATOX1-induced MMPs secretion and apoptosis in HAVSMCs. Lastly, overexpression of miR-133b through AAV9 significantly attenuated the progression of BAPN-induced AD in mice.

Conclusions

Our study suggests that inhibiting ATOX1 may reduce ECM degradation and cell apoptosis, thereby slowing the progression of AD, and highlights ATOX1 inhibition as a potential new strategy for AD treatment.

背景：主动脉夹层（AD）的发生与细胞外基质降解和血管平滑肌细胞（VSMCs）凋亡密切相关。抗氧化剂1 （ATOX1）是一种铜结合蛋白，其参与细胞外基质降解、VSMC凋亡和AD发病的确切机制仍有待进一步阐明。方法和结果：通过高通量测序，我们发现ATOX1在AD患者中表达显著增加。通过组织染色、RT-PCR和Western blot进一步验证，发现ATOX1在AD患者、AD小鼠模型和血管紧张素II （AngII）诱导的体外人主动脉血管平滑肌细胞（HAVSMCs）中表达升高。体外实验表明，沉默ATOX1或用DC_AC50药物抑制ATOX1可显著降低hasmcs中铜离子的表达和基质金属蛋白酶（MMPs）的分泌，同时减轻细胞凋亡。在β-氨基丙腈（BAPN）诱导的小鼠模型中，使用腺相关病毒载体9 （AAV9）靶向敲除平滑肌细胞中的ATOX1或药理抑制ATOX1可有效减缓AD的进展。此外，ATOX1的表达受miR-133b的直接调控，在AD患者的血清和主动脉组织中，miR-133b被发现显著下调，与ATOX1在AD中的上调呈负相关。MiR-133b mimic成功逆转了atox1诱导的hasmcs中MMPs分泌和凋亡的影响。最后，通过AAV9过表达miR-133b可显著减弱小鼠bapn诱导的AD的进展。结论：我们的研究表明，抑制ATOX1可能会减少细胞外基质降解和细胞凋亡，从而减缓AD的进展，并强调抑制ATOX1是一种潜在的治疗AD的新策略。

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引用次数: 0

HKDC1 promotes the H3K18 lactylation of the promoter of ORMDL3 to induce the activation of hepatic stellate cells in liver cirrhosis HKDC1促进ORMDL3启动子的H3K18乳酸化，诱导肝硬化肝星状细胞活化

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-18 DOI: 10.1016/j.bbadis.2025.168140

Yanan Zhang , Lei Li , Gaiqin Li , Junyuan Zhu , Zexue Qi , Chunqing Zhang

Purpose

We aimed to investigate the role and possible mechanism of action of hexokinase domain containing 1 (HKDC1) in liver cirrhosis.

Methods

Hepatic stellate cell (HSC) activation model was established in LX-2 cells by transforming growth factor (TGF)-βl stimulation. A mouse model of hepatic fibrosis was established using carbon tetrachloride (CCl₄) stimulation. HKDC1 expression was assessed using qRT-PCR, western blotting, and immunofluorescence. Hematoxylin and eosin (H&E) and Masson staining were used to assess liver injury and fibrosis. Changes in fibrosis markers were assessed using qRT-PCR, western blotting, and immunohistochemical staining. The effect of HKDC1 on glycolysis was evaluated by measuring the levels of extracellular acidification rate (ECAR), oxygen consumption rate (OCR), lactate, and related proteins.

Results

In liver cirrhosis tissues and activated HSCs, HKDC1 expression was upregulated. CCl₄-induced liver injury and fibrosis were inhibited by silencing of Hkdc1 in mice, as evidenced by the decrease of aspartate transaminase (AST), alanine transaminase (ALT), Collagen I, α-SMA, TGF-β1, and TIMP-1. Under TGF-β1 treatment, silencing of HKDC1 inhibited HSC activation and glycolysis, as evidenced by the reduce of Collagen I, α-SMA, TIMP-1, ECAR, lactate, HK2, LDHA, PKM2 and the increase of OCR. Mechanistically, silencing of HKDC1 reduced the levels of ORMDL3 and H3K18la proteins, and HKDC1 increased histone lactylation of the promoter of ORMDL3. ORMDL3 overexpression and lactate eliminated the effects of HKDC1 silencing on LX-2 cell activation.

Conclusion

HKDC1 silencing alleviates liver fibrosis and HSC activation by regulating glycolysis and decreasing histone lactylation of the promoter of ORMDL3.

目的探讨己糖激酶结构域1 （HKDC1）在肝硬化中的作用及其可能机制。方法采用转化生长因子(TGF)-β 1刺激LX-2细胞建立肝星状细胞（HSC）活化模型。采用四氯化碳（CCl4）刺激法建立小鼠肝纤维化模型。采用qRT-PCR、western blotting和免疫荧光检测HKDC1的表达。苏木精和伊红（H&；E）和Masson染色评估肝损伤和纤维化。使用qRT-PCR、western blotting和免疫组织化学染色评估纤维化标志物的变化。通过测量细胞外酸化率（ECAR）、耗氧量（OCR）、乳酸盐和相关蛋白的水平来评估HKDC1对糖酵解的影响。结果在肝硬化组织和活化的造血干细胞中，HKDC1表达上调。沉默Hkdc1可抑制ccl4诱导的小鼠肝损伤和纤维化，表现为天冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）、I型胶原蛋白、α-SMA、TGF-β1和TIMP-1的降低。TGF-β1处理下，沉默HKDC1抑制HSC活化和糖酵解，表现为胶原I、α-SMA、TIMP-1、ECAR、乳酸、HK2、LDHA、PKM2减少，OCR增加。机制上，HKDC1的沉默降低了ORMDL3和H3K18la蛋白的水平，HKDC1增加了ORMDL3启动子的组蛋白乳酸化。ORMDL3过表达和乳酸消除了HKDC1沉默对LX-2细胞活化的影响。结论hkdc1沉默通过调节ORMDL3启动子的糖酵解和降低组蛋白乳酸化来缓解肝纤维化和HSC活化。

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引用次数: 0

Unraveling the choline pathway in heart failure risk and outcomes: A systematic review and meta-analysis 揭示胆碱途径在心力衰竭风险和结果：一项系统回顾和荟萃分析。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-05 DOI: 10.1016/j.bbadis.2025.168103

Arveen Shokravi , Yuchen Luo , Simon W. Rabkin

Background

The objectives of this systematic review and meta-analysis were to (i) evaluate the relationship between circulating levels choline and its metabolites, phosphatidylcholine (PC), trimethylamine N-oxide (TMAO), betaine, and dimethylglycine (DMG) with heart failure (HF) development and its adverse clinical outcomes (ii) explore potential mechanisms that link them to HF.

Methods

A systematic search of MEDLINE, EMBASE, and PubMed was conducted.

Results

Nine prospective cohort studies (n = 267,569) were analysed. Elevated choline and PC were significantly associated with an increased incidence of HF respectively HR 1.33 (95 % CI 1.07–1.66, p = 0.0107) and HR 1.25 (95 % CI 1.16–1.34, p < 0.0001). In established HF, elevated betaine levels were significantly associated with a composite of adverse clinical outcomes (HR 1.15, 95 % CI 1.02–1.30, p = 0.0206). The molecular mechanisms linking choline and PC to HF include the hydrolysis of PC into lysophosphatidylcholine which can produce inflammation and cardiomyocyte apoptosis. Several metabolites and pathways are intriguing therapeutic targets, including lysophosphatidylcholine acyltransferase 1, phospholipase A2, choline trimethylamine lyase, and the phosphatidylethanolamine N-methyltransferase pathway.

Conclusions

Choline metabolites are implicated in HF development and progression. Understanding the mechanism whereby choline metabolism leads to HF may lead to novel therapeutic targets for HF management and prevention.

背景：目的是(i)评估循环胆碱及其代谢物、磷脂酰胆碱（PC）、三甲胺n -氧化物（TMAO）、甜菜碱和二甲基甘氨酸（DMG）与心力衰竭（HF）发展及其不良临床结局之间的关系（ii）探索它们与HF相关的潜在机制。方法：系统检索MEDLINE、EMBASE和PubMed。结果：对9项前瞻性队列研究（n = 267,569）进行了分析。升高的胆碱和PC分别与HF发生率增加显著相关，HR为1.33（95 % CI 1.07-1.66, p = 0.0107）和HR为1.25（95 % CI 1.16-1.34, p ）。了解胆碱代谢导致心衰的机制可能会导致新的心衰治疗靶点。

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引用次数: 0

FcRn: A novel target to attenuate rheumatoid cachexia in arthritic mice FcRn：减轻关节炎小鼠类风湿恶病质的新靶点。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-13 DOI: 10.1016/j.bbadis.2025.168141

Kristy Swiderski , Jessica Day , Cynthia Louis , Annabel Chee , Jennifer Trieu , Pranavie Vijayakumar , Jason Crisologo , Hongwei Qian , Paul Gregorevic , Ian P. Wicks , Gordon S. Lynch

•
Rheumatoid cachexia affects almost half of all rheumatoid arthritis (RA) patients, occurring early in disease and worsening in up to 48 % of patients despite resolution of arthritis.
•
Using the K/B × N serum transfer-induced arthritis (STIA) murine model of RA, we demonstrated that immunoglobulin G (IgG) accumulates in the interstitial space surrounding skeletal muscle fibers in arthritic mice.
•
Knockdown of the neonatal Fc receptor (FcRn), which regulates IgG half-life, partially attenuated skeletal muscle fiber atrophy in STIA mice.
•
FcRn inhibition may be a novel strategy to attenuate rheumatoid cachexia in RA and is worthy of further investigation.

•类风湿恶病质影响几乎一半的类风湿关节炎（RA）患者，发生在疾病早期，并在高达48%的患者中恶化，尽管关节炎消退。•使用K/B × N血清转移性关节炎（STIA）小鼠RA模型，我们证实免疫球蛋白G （IgG）在关节炎小鼠骨骼肌纤维周围间隙中积累。•新生儿Fc受体（FcRn）的敲低，其调节IgG半衰期，部分减轻了STIA小鼠骨骼肌纤维萎缩。•FcRn抑制可能是一种减轻类风湿恶病质的新策略，值得进一步研究。

引用次数: 0

Targeting the NLRP3 inflammasome signalling in acute myeloid leukemia: Mechanisms, therapeutics, and future directions 靶向NLRP3炎性小体信号在急性髓性白血病中的作用：机制、治疗方法和未来方向。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-21 DOI: 10.1016/j.bbadis.2025.168143

Sally H. Fayad , Alaa Mohamed Salah , Ayad A. Jaffa , Nadine Darwiche

Acute myeloid leukemia (AML) is one of the most frequent hematological malignancies. It is a complex and aggressive disease of undifferentiated hematopoietic progenitor cells, with high rates of relapse and drug resistance, posing significant clinical challenges. Emerging evidence underscores the critical role of inflammation in AML progression, with inflammasomes—key regulators of the inflammatory response—emerging as pivotal players in disease pathogenesis. Among these, the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome has gained particular attention due to its involvement in promoting leukemogenesis and chemoresistance. While inflammasomes have been previously studied in various cancer types, no comprehensive review to date has specifically addressed the role of the NLRP3 inflammasome in AML and its potential targeted therapy. Focusing on the NLRP3 inflammasome, we explore its contribution to AML pathogenesis and its therapeutic potential. We highlight preclinical natural and synthetic compounds, alongside clinical-stage and clinically approved drugs that target the NLRP3 inflammasome signalling pathway and components. We address the challenges and limitations of these promising compounds and drugs, while highlighting recent advancements such as the synthesis of novel and derivatives designed to improve their efficacy. Finally, we discuss future research directions aimed at deepening our understanding of the NLRP3 inflammasome and identifying novel and improved therapeutic outcomes against AML.

急性髓系白血病（AML）是最常见的血液系统恶性肿瘤之一。它是一种复杂和侵袭性的未分化造血祖细胞疾病，具有高复发率和耐药性，给临床带来了重大挑战。新出现的证据强调了炎症在AML进展中的关键作用，炎症小体-炎症反应的关键调节因子-在疾病发病机制中扮演着关键角色。其中，NOD-、LRR-和含pyrin结构域3 （NLRP3）炎症小体因其参与促进白血病发生和化疗耐药而受到特别关注。虽然炎性小体在各种癌症类型中已经被研究过，但迄今为止还没有全面的综述专门针对NLRP3炎性小体在AML中的作用及其潜在的靶向治疗。以NLRP3炎性小体为重点，探讨其在AML发病机制中的作用及其治疗潜力。我们重点关注临床前天然和合成化合物，以及临床阶段和临床批准的靶向NLRP3炎症小体信号通路和成分的药物。我们解决了这些有前途的化合物和药物的挑战和局限性，同时强调了最近的进展，如新合成和衍生物的设计，以提高其功效。最后，我们讨论了未来的研究方向，旨在加深我们对NLRP3炎症小体的理解，并确定新的和改进的AML治疗结果。

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引用次数: 0

Calpain activation disrupts ER-Phagy and leads to mitochondrial damage in hearts treated with isoproterenol 在异丙肾上腺素治疗的心脏中，钙蛋白酶激活破坏er吞噬并导致线粒体损伤。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-11-28 DOI: 10.1016/j.bbadis.2025.168127

Qun Chen , Ling Li , Jeremy Thompson , Ying Hu , Belinda Willard , Edward J. Lesnefsky

The endoplasmic reticulum (ER) is a dynamic organelle whose homeostasis is maintained by ER-phagy (ERPG). Under conditions of ER stress, calcium-dependent cysteine proteases—specifically calpain 1 and calpain 2 (CPN1/2)—are activated and contribute to mitochondrial damage. Isoproterenol (ISO) administration is a widely used experimental model for inducing cardiac dysfunction. In this study, we hypothesize that impaired ERPG worsens ER stress in ISO-treated hearts, leading to mitochondrial dysfunction through the activation of CPN1/2. Male C57BL/6 mice (2–3 months old) received ISO at a dose of 100 mg/kg via daily intraperitoneal (IP) injection for five consecutive days. Cardiac function, ER stress, and mitochondrial function were assessed before ISO treatment, and at 1-, 2-, and 4- weeks following exposure. Cardiac dysfunction was evident two weeks after ISO administration. ER stress began to increase one week after ISO treatment and continued to intensify at 2 and 4 weeks. Activation of cytosolic CPN1/2 was observed at 1 week. The content of FAM134B—a key regulator of ERPG—was reduced by 2 weeks post-treatment. Incubation experiments showed that purified CPN1 cleaves FAM134B, supporting its role as a direct target. Mitochondrial respiration, including cytochrome oxidase activity, declined two weeks after ISO exposure. This decline was associated with a loss of cytochrome c and reduced levels of ferrochelatase, both contributing to impaired mitochondrial oxidative capacity. These findings suggest that reducing ER stress may be an effective therapeutic strategy to mitigate contractile dysfunction with cardiac disease.

内质网（ER）是一个动态的细胞器，内质网吞噬（ERPG）维持其稳态。在内质网应激条件下，钙依赖性半胱氨酸蛋白酶-特别是钙蛋白酶1和钙蛋白酶2 (CPN1/2)-被激活并导致线粒体损伤。异丙肾上腺素（isoterenol， ISO）是一种广泛使用的诱导心功能障碍的实验模型。在这项研究中，我们假设受损的ERPG加重了iso处理心脏的内质网应激，通过激活CPN1/2导致线粒体功能障碍。雄性C57BL/6小鼠（2-3 月龄）每天腹腔注射100 mg/kg剂量的ISO，连续5天。心功能、内质网应激和线粒体功能在ISO治疗前和暴露后1周、2周和4周进行评估。给药后2周心功能不全明显。内质网应激在ISO处理后1周开始增加，并在 第2周和第4周继续增强。在1 周观察到胞浆CPN1/2的活化。治疗后2 周，erpg的关键调节因子fam134b的含量降低。培养实验表明，纯化的CPN1可切割FAM134B，支持其作为直接靶点的作用。线粒体呼吸，包括细胞色素氧化酶活性，在暴露于ISO两周后下降。这种下降与细胞色素c的丧失和铁螯合酶水平的降低有关，两者都导致线粒体氧化能力受损。这些发现表明，减少内质网应激可能是一种有效的治疗策略，以减轻心脏疾病的收缩功能障碍。

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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 : 2026-03-01 Epub 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。

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引用次数: 0

Binding of human low-density lipoproteins to type-I collagen is synergistic with the pro-atherogenic lipoprotein remodeling 人低密度脂蛋白与i型胶原蛋白的结合与促动脉粥样硬化脂蛋白重塑具有协同作用。

IF 4.2 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular basis of disease

Pub Date : 2026-03-01 Epub Date: 2025-12-17 DOI: 10.1016/j.bbadis.2025.168142

Shobini Jayaraman , Kyeongseo Choi , Antonio Pérez , Inka Miñambres , Jose Luis Sánchez-Quesada , Olga Gursky

Low-density lipoprotein (LDL) entrapment in the extracellular matrix of the arterial intima is an established early trigger of atherosclerosis. Though much is known about LDL binding to arterial proteoglycans, the binding to other matrix components remains underexplored. This study focuses on LDL interactions with type-I collagen (Col-I), a major extracellular matrix protein found in atherosclerotic lesions. Human normolipidemic LDL, which has been oxidized or lipolyzed in vitro, and naturally occurring plasma LDL subclasses differing in size and charge are explored, along with LDL from patients with type-2 diabetes or obesity before and after treatment. To understand how these lipoproteins interact with Col-I, we quantify their binding to collagen-coated microwell plates using enzyme-linked immunosorbent assay. The mechanistic underpinnings are probed by a multipronged approach using the methods of chromatography, spectroscopy, microscopy and others. The results reveal that intact LDL binds Col-I in a cooperative dose-dependent manner. The binding is synergistic with pro-atherogenic LDL modifications including aggregation, oxidation and lipolysis. The pro-atherogenic subclasses of small dense LDL and electronegative LDL show enhanced Col-I binding; conversely, Col-I binding induces LDL remodeling to generate smaller and more electronegative particles. This synergy suggests a potential causal role of LDL–Col-I interactions in atherogenesis. Moreover, our results suggest that LDL binding to Col-I provides a biomarker and a sensitive treatment readout for the risk of atherosclerosis in patients with metabolic diseases such as diabetes and obesity.

动脉内膜细胞外基质中的低密度脂蛋白（LDL）被确定为动脉粥样硬化的早期触发因素。尽管人们对LDL与动脉蛋白聚糖的结合了解甚多，但其与其他基质成分的结合仍未得到充分研究。本研究的重点是LDL与i型胶原蛋白（ColI）的相互作用，i型胶原蛋白是动脉粥样硬化病变中发现的主要细胞外基质蛋白。研究了在体外氧化或脂解的人正常血脂LDL，以及在治疗前后2型糖尿病或肥胖患者的LDL的大小和电荷不同的天然血浆LDL亚类。为了了解这些脂蛋白如何与大肠杆菌相互作用，我们使用酶联免疫吸附法定量了它们与胶原包被微孔板的结合。其机制基础是通过使用色谱、光谱学、显微镜和其他方法的多管齐下的方法来探索的。结果表明，完整的LDL以一种剂量依赖的方式与col - 1结合。这种结合与促动脉粥样硬化的LDL修饰有协同作用，包括聚集、氧化和脂解。小密度LDL和电负性LDL的促动脉粥样硬化亚类显示出增强的coli结合；相反，col - 1结合诱导LDL重塑，产生更小、电负性更强的颗粒。这种协同作用提示ldl - col - 1相互作用在动脉粥样硬化发生中的潜在因果作用。此外，我们的研究结果表明，LDL与col - 1的结合为糖尿病和肥胖等代谢性疾病患者的动脉粥样硬化风险提供了一种生物标志物和敏感的治疗读数。

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