Biochimica et biophysica acta. Molecular cell research最新文献

英文中文

Shielding retinal pigment epithelium cells from high glucose-induced oxidative stress: the protective effect of phospholipase D (PLD) pathway inhibition 保护视网膜色素上皮细胞免受高糖诱导的氧化应激：磷脂酶D （PLD）途径抑制的保护作用。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-01-28 DOI: 10.1016/j.bbamcr.2026.120121

María S. Echevarría , Paula E. Tenconi , Vicente Bermúdez , Jorgelina M. Calandria , Nicolas G. Bazan , Melina V. Mateos

The retinal pigment epithelium (RPE) performs key roles in preserving retinal integrity and must continuously manage oxidative stress (OS). We previously demonstrated that the canonical phospholipase D isoforms, PLD1 and PLD2, mediate the RPE inflammatory response triggered by inflammatory injury. This study explores the mechanisms of modulation of OS mediated by PLD inhibition in RPE cells exposed to high glucose (HG) levels.

ARPE-19, D407 and the novel human RPE cell line ABC were cultured under HG (33 mM) or normal glucose (NG, 5.5 mM) conditions. To inhibit PLD1, PLD2, and NADPH oxidase (NOX), VU0359595 (PLD1i), VU0285655-1 (PLD2i), and diphenyleneiodonium chloride (DPI) were used, respectively. HG exposure significantly increased reactive oxygen species (ROS) levels and reduced mitochondrial membrane potential (MMP) in ARPE-19 and D407 cells. These effects were prevented by PLD1i and PLD2i in an Nrf-2 and cyclooxygenase-2 -independent manner. In ARPE-19 cells, DPI prevented OS induced by HG as well as the stress triggered by the combination of phosphatidic acid + diacylglycerol, bioactive lipids generated through the PLD pathway-. Similarly, HG elevated ROS levels in ABC cells, and this increase was prevented by PLD1i and DPI. RNAseq analysis showed differential expression of NOX family members (NOX1,2 and 4 and DUOX1 and 2) in ARPE-19 and ABC cells.

Our results demonstrate that PLDs inhibition prevent HG-induced OS in RPE cells, possibly by reducing NOX activity. The PLD pathway constitutes a novel pharmacological target to simultaneously mitigate OS and the inflammatory response, two hallmarks of retinal degenerative diseases.

视网膜色素上皮（RPE）在保护视网膜完整性方面发挥着关键作用，必须持续管理氧化应激（OS）。我们之前证明了典型磷脂酶D亚型PLD1和PLD2介导炎症损伤引发的RPE炎症反应。本研究探讨了暴露于高葡萄糖（HG）水平的RPE细胞中PLD抑制介导的OS调节机制。ARPE-19、D407和新型人RPE细胞系ABC分别在HG（33 mM）和正常葡萄糖（NG, 5.5 mM）条件下培养。分别用VU0359595 （PLD1i）、VU0285655-1 （PLD2i）和二苯二氯铵（DPI）抑制PLD1、PLD2和NADPH氧化酶（NOX）。HG暴露显著增加ARPE-19和D407细胞的活性氧（ROS）水平，降低线粒体膜电位（MMP）。PLD1i和PLD2i以不依赖于Nrf-2和环氧化酶-2的方式阻止了这些作用。在ARPE-19细胞中，DPI可以阻止HG诱导的OS以及磷脂酸+二酰基甘油（PLD途径产生的生物活性脂质）联合引发的应激。同样，HG升高ABC细胞中的ROS水平，PLD1i和DPI可以阻止这种升高。RNAseq分析显示，NOX家族成员（NOX1、2、4和DUOX1、2）在ARPE-19和ABC细胞中的表达存在差异。我们的研究结果表明，PLDs抑制可能通过降低NOX活性来防止hg诱导的RPE细胞OS。PLD通路构成了一个新的药理学靶点，可以同时减轻OS和炎症反应，这是视网膜退行性疾病的两个标志。

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引用次数: 0

The role of cytokines in cytokine release syndrome (CRS) after CAR T cell therapy 细胞因子在CAR - T细胞治疗后细胞因子释放综合征（CRS）中的作用。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-01-23 DOI: 10.1016/j.bbamcr.2026.120115

Kathrin Gabriel , Lucie Heinzerling , Louisa von Baumgarten , Marion Subklewe , Sebastian Kobold

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape for hematological malignancies. However, cytokine release syndrome (CRS) remains a common and potentially severe toxicity, significantly affecting patient safety and requiring intensive clinical management. This review provides a focused synthesis on the role of cytokines in CRS after CAR T cell therapy, integrating recent mechanistic insights with clinical implications. We delineate the cellular and molecular pathways involving key cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor α (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF), describing their sources, downstream signaling events, and effects on target tissues. By bridging basic cytokine biology with clinical aspects and therapeutic strategies, this review aims to provide a comprehensive framework for understanding the role of cytokines in CRS pathophysiology, ultimately supporting the development of safer and more effective CAR T cell therapies.

嵌合抗原受体（CAR） T细胞疗法已经改变了血液系统恶性肿瘤的治疗前景。然而，细胞因子释放综合征（CRS）仍然是一种常见且潜在严重的毒性，严重影响患者安全，需要强化临床管理。本文综述了细胞因子在CAR - T细胞治疗后的CRS中的作用，并结合了最近的机制见解和临床意义。我们描述了涉及关键细胞因子如白细胞介素-1 （IL-1）、白细胞介素-6 （IL-6）、干扰素γ (IFN-γ)、肿瘤坏死因子α (TNF-α)和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的细胞和分子途径，描述了它们的来源、下游信号事件和对靶组织的影响。通过将基础细胞因子生物学与临床方面和治疗策略联系起来，本综述旨在为理解细胞因子在CRS病理生理中的作用提供一个全面的框架，最终支持开发更安全、更有效的CAR - T细胞疗法。

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引用次数: 0

Destabilization of lipoma-preferred partner by TGF-β-induced O-GlcNAcylation promotes hepatocellular carcinoma metastasis TGF-β-诱导的o - glcn酰化破坏脂肪瘤首选伴侣的稳定性，促进肝癌转移。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-01-24 DOI: 10.1016/j.bbamcr.2026.120117

De-ao Gong , Qin Yang , Yan-lai Zhang , Lu-yi Huang , Ni Tang , Kai Wang

Metastatic dissemination drives the lethal progression of hepatocellular carcinoma (HCC). A comprehensive elucidation of the post-translational modifications involved in this process is anticipated to facilitate the development of more effective strategies for inhibiting tumor cell dissemination. Here, we identified the lipoma-preferred partner (LPP) as an unexpected metastasis suppressor that is specifically downregulated in HCC. Mechanistically, transforming growth factor-β1 (TGF-β1) stabilizes glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway, thereby elevating global O-GlcNAcylation levels. O-GlcNAc transferase (OGT) subsequently modifies LPP protein at serine 33 and 35, priming its ubiquitination-dependent proteasomal degradation. This degradation, mediated by the ubiquitin-protein ligase E3A (UBE3A), occurs at lysine 108 (K108) of LPP, which facilitates HCC cell migration and invasion both in vitro and in vivo. Mutagenesis of these glycosylation sites markedly attenuates HCC cell motility, invasion, and pulmonary colonization in tail-vein models. Conversely, LPP depletion accelerates metastatic outgrowth and associates with reduced patient survival. Collectively, our findings reveal a TGF-β/GFAT1/LPP axis that couples metabolic reprogramming to metastatic competence, and highlight O-GlcNAcylation blockade or targeted stabilization of LPP as potential therapeutic strategies against metastatic HCC.

转移性传播驱动肝细胞癌（HCC）的致命进展。对这一过程中涉及的翻译后修饰的全面阐明有望促进开发更有效的抑制肿瘤细胞传播的策略。在这里，我们发现脂肪瘤首选伴侣（LPP）是一种意想不到的转移抑制因子，在HCC中特异性下调。从机制上讲，转化生长因子-β1 （TGF-β1）稳定己糖胺生物合成途径的限速酶谷氨酰胺-果糖-6-磷酸转氨酶1 (GFAT1)，从而提高全球o - glcnac酰化水平。O-GlcNAc转移酶（OGT）随后修饰LPP蛋白的丝氨酸33和35，启动其泛素化依赖的蛋白酶体降解。这种降解是由泛素蛋白连接酶E3A （UBE3A）介导的，发生在LPP的赖氨酸108 （K108）上，促进了肝癌细胞在体外和体内的迁移和侵袭。在尾静脉模型中，这些糖基化位点的突变显著减弱HCC细胞的运动性、侵袭性和肺定植。相反，LPP耗竭会加速转移性生长，并与患者生存期降低相关。总之，我们的研究结果揭示了TGF-β/GFAT1/LPP轴将代谢重编程与转移能力结合在一起，并强调了o - glcn酰化阻断或靶向稳定LPP是治疗转移性HCC的潜在治疗策略。

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引用次数: 0

Differential inclusion formation of an aggregation-prone protein reveals differences in the proteostasis capacity of neuronal cell lines 一种聚集倾向蛋白的不同包涵形成揭示了神经细胞系中蛋白质平衡能力的差异。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-02-17 DOI: 10.1016/j.bbamcr.2026.120124

Shannon McMahon , Dezerae Cox , Flora Cheng , Albert Lee , Justin.J. Yerbury , Heath Ecroyd

Maintaining proteome integrity is essential for cellular function and survival. Disruptions in proteostasis lead to the aggregation of proteins into inclusions, a process that underlies many neurodegenerative diseases. To quantitatively assess the proteostasis capacity of neuronal cells, we employed an aggregation-prone double mutant form of firefly luciferase (denoted Fluc^DM) as a reporter protein. We compared two commonly used neuronal cell lines, mouse neuroblastoma cells (Neuro-2a) and a motor neuron-like hybrid line (NSC-34), to evaluate their ability to prevent the aggregation of proteins into intracellular inclusions. We observed a significantly greater propensity of Fluc^DM to form inclusions in NSC-34 cells compared to Neuro-2a cells. This suggests a reduced capacity of NSC-34 cells for managing aggregation-prone proteins. Proteomic profiling of Fluc^DM inclusions purified from both cell types revealed cell-type-specific engagement of the proteostasis machinery with aggregation-prone proteins. Comparing the proteomic profiles of key arms of the proteostasis network between these two cell lines revealed that the endoplasmic reticulum (ER) unfolded protein response is differentially expressed. This study establishes a quantitative platform for assessing cellular proteostasis capacity and underscores the importance of cell-type context in proteome maintenance. These insights have implications for understanding the selective vulnerability of neurons in protein misfolding disorders.

维持蛋白质组的完整性对细胞功能和存活至关重要。蛋白质平衡的破坏导致蛋白质聚集成包涵体，这一过程是许多神经退行性疾病的基础。为了定量评估神经元细胞的蛋白质抑制能力，我们使用了一种易于聚集的双突变形式的萤火虫荧光素酶（fludm）作为报告蛋白。我们比较了两种常用的神经细胞系，小鼠神经母细胞瘤细胞（神经-2a）和运动神经元样杂交细胞系（NSC-34），以评估它们阻止蛋白质聚集到细胞内包涵体的能力。我们观察到，与neuro2a细胞相比，FlucDM在NSC-34细胞中形成包涵体的倾向明显更大。这表明NSC-34细胞管理易聚集蛋白的能力降低。从两种细胞类型中纯化的FlucDM包涵体的蛋白质组学分析显示，蛋白质静止机制与易于聚集的蛋白质具有细胞特异性。比较这两种细胞系蛋白质静止网络关键臂的蛋白质组学特征，发现内质网（ER）未折叠蛋白反应的表达存在差异。本研究建立了一个定量的平台来评估细胞的蛋白质平衡能力，并强调了细胞类型背景在蛋白质组维持中的重要性。这些见解对理解蛋白质错误折叠障碍中神经元的选择性脆弱性具有重要意义。

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引用次数: 0

ADAM10 and ADAM17 differently mediate induced pulmonary ACE release by either direct proteolysis or indirect upregulation protein synthesis ADAM10和ADAM17通过直接蛋白水解或间接上调蛋白合成介导不同程度的肺ACE释放。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-01-12 DOI: 10.1016/j.bbamcr.2026.120112

Yan Yu , Aaron Babendreyer , Alessa Pabst , Anna Michely , Marie Tauscher , Christian Martin , Mark P. Kühnel , Danny D. Jonigk , Stefan Düsterhöft , Andreas Ludwig

Angiotensin-converting enzyme (ACE) is expressed on lung endothelium and can promote hypertension and cardiovascular diseases. By the activity of the metalloproteinase ADAM10 ACE can be constitutively released from the cell membrane as soluble protease. The aim of this study was to further investigate the mechanisms underlying the enhanced production of soluble ACE under pathological conditions. Using in vitro models of primary human pulmonary microvascular endothelial cells (HPMECs) and primary human umbilical vein endothelial cells (HUVECs), as well as ex vivo models of human and murine precision-cut lung slices (PCLS), we examined ACE release in response to inflammatory stimuli, hypoxia, and protein kinase C (PKC) activation, in the presence or absence of ADAM10 and ADAM17 inhibitors. Our findings demonstrate that ADAM10 is the primary sheddase responsible for inducible ACE release, while ADAM17 contributes to ACE shedding via paracrine transcriptional induction through soluble mediators. Moreover, ACE release was differentially induced by lipopolysaccharide (LPS) and hypoxia in a manner dependent on the cellular or tissue context and exhibited species-specific differences in response to the tested stimuli. Importantly, inducibly released ACE displays enhanced catalytic activity attributable to its increased extracellular concentration. Collectively, our data reveal, for the first time, that inducible ACE release is directly mediated by ADAM10, indirectly facilitated by ADAM17, and is influenced by tissue-, context-, and species-dependent factors. This complex regulation of soluble ACE release in pathological settings may be involved in fine tuning vascular pathologies.

血管紧张素转换酶（ACE）在肺内皮表达，可促进高血压和心血管疾病的发生。通过金属蛋白酶ADAM10的活性，ACE可作为可溶性蛋白酶组成性地从细胞膜释放。本研究的目的是进一步探讨病理条件下可溶性ACE生成增强的机制。利用原代人肺微血管内皮细胞（hpmec）和原代人脐静脉内皮细胞（HUVECs）的体外模型，以及人和鼠精确切割肺切片（PCLS）的体外模型，我们检测了在存在或不存在ADAM10和ADAM17抑制剂的情况下，ACE释放对炎症刺激、缺氧和蛋白激酶C （PKC）激活的响应。我们的研究结果表明，ADAM10是负责诱导ACE释放的主要脱落酶，而ADAM17通过可溶性介质通过旁分泌转录诱导来促进ACE的脱落。此外，根据细胞或组织环境的不同，脂多糖（LPS）和缺氧诱导ACE释放的方式也不同，并且在对测试刺激的反应中表现出物种特异性差异。重要的是，诱导释放的ACE由于其细胞外浓度的增加而表现出增强的催化活性。总的来说，我们的数据首次揭示了诱导性ACE释放由ADAM10直接介导，ADAM17间接促进，并受组织、环境和物种依赖因素的影响。病理环境中可溶性ACE释放的复杂调控可能与精细调节血管病变有关。

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引用次数: 0

Sox9-dependent acquisition of a drug resistant “memory state” induces reciprocal expression of Sox6 and Sox7 in BRAF melanoma 在BRAF黑色素瘤中，sox9依赖性耐药“记忆状态”的获得诱导了Sox6和Sox7的相互表达。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-01-22 DOI: 10.1016/j.bbamcr.2026.120118

John Abou-Hamad , Samuel Delisle , Brennan Garland , Mohammed Hersi , David Cook , Luc A. Sabourin

In melanoma, SOX9 and SOX10 are markers of the mesenchymal and melanocytic state, respectively. Using a panel of BRAF^V600E positive YUMM lines, we find that, following chronic vemurafenib treatment, SOX10 is lost whereas SOX9 is induced. Overexpression or knock-down of either SOX9 or SOX10 had no impact on vemurafenib sensitivity. However, we find that SOX9 is necessary to program a vemurafenib-resistance memory state following a drug holiday in vitro. RNA-Seq studies show that the loss of Sox10 represents an intermediate state that is accompanied by the loss of Sox6 and the induction of Sox7, Sox9 and other phenotype switching markers. However, SOX7 expression is not sufficient to induce vemurafenib resistance. Upon acquired drug resistance, we observed differential chromatin accessibility in the Sox9 and Sox10 upstream regions, supporting their activation and repression, respectively. Overall, our data show that the loss of SOX10 and SOX9 induction are critical to program drug resistance. Furthermore, we show that the YUMM cell lines represent a good murine model to investigate transitions to an acquired drug resistant state.

在黑色素瘤中，SOX9和SOX10分别是间质和黑素细胞状态的标记物。使用一组BRAFV600E阳性的YUMM细胞系，我们发现，在慢性vemurafenib治疗后，SOX10丢失，而SOX9被诱导。SOX9或SOX10的过表达或敲低对vemurafenib的敏感性没有影响。然而，我们发现SOX9是在体外药物假期后编程vemurafenib耐药记忆状态所必需的。RNA-Seq研究表明，Sox10的缺失代表了一种中间状态，伴随着Sox6的缺失和Sox7、Sox9等表型切换标记的诱导。然而，SOX7表达不足以诱导vemurafenib耐药。在获得性耐药后，我们观察到Sox9和Sox10上游区域染色质可及性的差异，分别支持它们的激活和抑制。总的来说，我们的数据表明，SOX10和SOX9诱导的缺失对程序耐药至关重要。此外，我们发现YUMM细胞系是研究获得性耐药状态转变的良好小鼠模型。

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引用次数: 0

Neutrophil-mediated modulation of tumor angiogenesis: From proangiogenic mediators to extracellular vesicles 中性粒细胞介导的肿瘤血管生成调节：从促血管生成介质到细胞外囊泡。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-02-23 DOI: 10.1016/j.bbamcr.2026.120126

Weronika Jurczyk , Jadwiga Jablonska , Mateusz Smolarz

Angiogenesis is a tightly controlled physiological process that enables the formation of new blood vessels. Under normal conditions, it is regulated by a balance between pro- and anti-angiogenic signals. In cancer, this equilibrium is disrupted, and angiogenesis becomes a pathological mechanism that supports tumor growth, progression, and metastasis. The process is orchestrated by a variety of cells, including endothelial cells (EC), fibroblasts, macrophages, platelets, neutrophils, and cancer cells, which release chemical mediators. Among them, growth factors such as VEGF, FGF, PDGF, angiopoietins, and TGF-β play a central role by activating signaling pathways that stimulate endothelial proliferation, migration, survival, and extracellular matrix (ECM) remodeling. Their activity drives the “angiogenic switch,” a hallmark of early tumor development. Neutrophils, the most abundant immune cells in circulation, exert a dual influence on this process. Pro-tumor neutrophils enhance angiogenesis through the secretion of VEGF-A, TGF-β, MMP-9, IL-8, and the release of neutrophil extracellular traps, facilitating vascular permeability and tumor progression. Conversely, anti-tumor neutrophils release TNF-α, IL-12, and chemokines such as CXCL9/10, which inhibit angiogenesis and restrain tumor expansion. Recently, small extracellular vesicles (sEVs) have emerged as critical mediators of intercellular communication. Neutrophil-derived sEVs transport proangiogenic miRNAs, proteins, and signaling molecules that influence endothelial activation, epithelial-to-mesenchymal transition, therapy resistance, and metastatic potential. Given their unique molecular cargo, they represent potential modulators of tumor angiogenesis, although studies in this area remain limited. This review summarizes the principal mechanisms of angiogenesis, the multifaceted role of neutrophils in shaping tumor vasculature, and the emerging contribution of neutrophil-derived sEVs.

血管生成是一个严格控制的生理过程，使新血管的形成成为可能。在正常情况下，它是由促血管生成和抗血管生成信号之间的平衡调节的。在癌症中，这种平衡被破坏，血管生成成为支持肿瘤生长、进展和转移的病理机制。这个过程是由多种细胞精心策划的，包括内皮细胞（EC）、成纤维细胞、巨噬细胞、血小板、中性粒细胞和癌细胞，它们释放化学介质。其中，生长因子如VEGF、FGF、PDGF、血管生成素和TGF-β通过激活刺激内皮细胞增殖、迁移、存活和细胞外基质（ECM）重塑的信号通路发挥核心作用。它们的活动驱动“血管生成开关”，这是早期肿瘤发展的标志。中性粒细胞是循环中最丰富的免疫细胞，在这一过程中发挥着双重作用。促瘤中性粒细胞通过分泌VEGF-A、TGF-β、MMP-9、IL-8和释放中性粒细胞胞外陷阱，促进血管通透性和肿瘤进展，促进血管生成。相反，抗肿瘤中性粒细胞释放TNF-α、IL-12和趋化因子如CXCL9/10，抑制血管生成和肿瘤扩张。最近，小细胞外囊泡（sev）已成为细胞间通讯的重要介质。中性粒细胞衍生的sev运输促血管生成的mirna、蛋白质和信号分子，影响内皮活化、上皮到间质转化、治疗耐药性和转移潜能。鉴于其独特的分子载体，它们代表了肿瘤血管生成的潜在调节剂，尽管在这一领域的研究仍然有限。本文综述了血管生成的主要机制，中性粒细胞在形成肿瘤血管系统中的多方面作用，以及中性粒细胞衍生的sev的新贡献。

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引用次数: 0

Matrix stiffness-induced NARF promotes hepatocellular carcinoma progression by enhancing LEF1-mediated transcription 基质刚度诱导的NARF通过增强lef1介导的转录促进肝细胞癌的进展。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-02-06 DOI: 10.1016/j.bbamcr.2026.120122

Xuelian Xiao, Kangsheng Tu

Liver fibrosis and cirrhosis generate a stiff extracellular matrix (ECM) niche that is closely associated with hepatocellular carcinoma (HCC) initiation and progression. Although multiple pathways and molecules are implicated in ECM rigidity-induced mechanical force transduction, the precise mechanism by which ECM rigidity drives HCC progression remain to be fully elucidated. In this study, we identified nuclear prelamin A recognition factor (NARF) as a novel matrix stiffness-responsive gene, whose transcription is directly regulated by the mechanosensor Yes-associated protein (YAP). Clinically, NARF exhibited high expressions in HCC tissues, and its overexpression was closely correlated with poor prognostic outcomes in HCC patients. Functionally, NARF knockdown significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells in vitro, whereas NARF overexpression enhanced these cellular processes. NARF silencing attenuated HCC cell growth and lung metastasis in vivo. RNA-sequencing analysis revealed a strong correlation of NARF with Wnt signaling activation. Further experiments confirmed that NARF positively regulated the expression of key Wnt target genes (MYC, CCND1, SNAIL, and TWIST1) in HCC cells. Mechanistically, NARF recruited acetyltransferase EP300 to enhance H3K27 acetylation at lymphoid enhancer binding factor 1 (LEF1)-binding sites, thereby amplifying LEF1-dependent transcriptional activity. LEF1 knockdown markedly abrogated NARF-mediated oncogenic activity in vitro and in vivo, confirming LEF1 as a critical downstream effector of NARF. Collectively, our findings identify NARF as stiffness-responsive driver that is transcriptionally regulated by YAP protein in HCC. By activating LEF1-mediated Wnt signaling in an EP300 dependent manner, NARF promotes HCC growth and metastasis, highlighting its potential as a prognostic biomarker and therapeutic target for HCC.

肝纤维化和肝硬化产生坚硬的细胞外基质（ECM）生态位，与肝细胞癌（HCC）的发生和发展密切相关。尽管ECM刚性诱导的机械力转导涉及多种途径和分子，但ECM刚性驱动HCC进展的确切机制仍有待完全阐明。在这项研究中，我们发现核前纤层蛋白A识别因子（NARF）是一种新的基质刚度响应基因，其转录由机械传感器yes相关蛋白（YAP）直接调控。临床上，NARF在HCC组织中高表达，其过表达与HCC患者预后不良密切相关。在功能上，NARF敲低可显著抑制体外HCC细胞的增殖、迁移、侵袭和上皮-间质转化（EMT），而NARF过表达可增强这些细胞过程。在体内，NARF沉默可减弱HCC细胞的生长和肺转移。rna测序分析显示，NARF与Wnt信号激活有很强的相关性。进一步实验证实，NARF正调控肝癌细胞中Wnt关键靶基因MYC、CCND1、SNAIL、TWIST1的表达。从机制上讲，NARF招募乙酰转移酶EP300增强H3K27在淋巴增强子结合因子1 （LEF1）结合位点的乙酰化，从而增强LEF1依赖的转录活性。在体外和体内，敲低LEF1显著消除了NARF介导的致癌活性，证实了LEF1是NARF的关键下游效应物。总的来说，我们的研究结果确定了NARF是HCC中由YAP蛋白转录调节的刚度响应驱动因子。通过以EP300依赖的方式激活lef1介导的Wnt信号，NARF促进HCC的生长和转移，突出了其作为HCC预后生物标志物和治疗靶点的潜力。

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引用次数: 0

USP49 regulates lipid metabolism in hepatocellular carcinoma by stabilizing RACK1 to promote tumor proliferation and migration USP49通过稳定RACK1来调节肝细胞癌的脂质代谢，促进肿瘤的增殖和迁移。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-01-08 DOI: 10.1016/j.bbamcr.2026.120107

Weikang Xu , Jijun Shan , Jifei Wang , Yudi Zhou , Yiming Ouyang , Yananlan Chen , Qiyang Zhou

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options. While ubiquitin-specific peptidase 49 (USP49) has been implicated in various cancers, its role in HCC is unclear. Here, we found that USP49 is upregulated in HCC tissues and associated with poor prognosis. Functional assays demonstrated that USP49 promotes HCC proliferation and migration both in vitro and in vivo. Mechanistically, USP49 directly interacts with and deubiquitinates RACK1, thereby stabilizing it. This stabilization leads to RACK1-driven transcriptional activation of key fatty acid metabolic enzymes, enhancing triglyceride synthesis and fueling tumor growth through metabolic reprogramming. Collectively, our study identifies the USP49/RACK1 axis as a critical driver of HCC progression and nominates USP49 as a promising therapeutic target.

肝细胞癌（HCC）仍然是一种致命的恶性肿瘤，治疗选择有限。虽然泛素特异性肽酶49 （USP49）与多种癌症有关，但其在HCC中的作用尚不清楚。本研究中，我们发现USP49在HCC组织中表达上调，并与预后不良相关。功能分析表明，USP49在体外和体内都能促进HCC的增殖和迁移。在机制上，USP49直接与RACK1相互作用并使其去泛素化，从而使其稳定。这种稳定导致rack1驱动的关键脂肪酸代谢酶的转录激活，增强甘油三酯合成并通过代谢重编程促进肿瘤生长。总的来说，我们的研究确定了USP49/RACK1轴是HCC进展的关键驱动因素，并提名USP49为有希望的治疗靶点。

引用次数: 0

ATM kinase phosphorylates HSP90 on T297 changing its conformation dynamics and promoting its interaction with HER2 receptor tyrosine kinase ATM激酶磷酸化T297上的HSP90，改变其构象动力学并促进其与HER2受体酪氨酸激酶的相互作用。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-03-01 Epub Date: 2026-01-09 DOI: 10.1016/j.bbamcr.2026.120110

Giulia Fianco , Irene Taddei , Veronica Oropallo , Claudia Contadini , Alessandra Ferri , Laura Coculo , Stefano A. Serapian , Giorgio Colombo , Venturina Stagni , Daniela Barilà

Heat Shock Protein 90 (HSP90) is an essential molecular chaperone whose activity is regulated not only by co-chaperones but also by distinct post-translational modifications. Interestingly, its chaperone activity is essential for the stability of several oncogenes, among which the receptor tyrosine kinase HER2. HER2 is overexpressed in 20–30% of breast and ovarian cancers. Its overexpression triggers proliferative and transforming pathways aberrant activation and therefore frequently correlates with invasive and poor prognostic features, and associates with shorter patient survival. Of note, HSP90 inhibitors have been studied in HER2-positive breast cancer and have shown promising results. Unexpectedly, we previously reported that ATM promotes the interaction of HER2 with HSP90 therefore sustaining HER2 protein stability and tumorigenicity.

To further investigate the interplay between HER2-HSP90 and ATM, we tested the hypothesis that ATM could phosphorylate HSP90. We confirmed that ATM activation can induce the phosphorylation of HSP90 in HER2 positive breast cancer models. Point mutagenesis showed that T297 is the major site targeted by ATM kinase and importantly the unphosphorylatable mutant HSP90-T297A displays a reduced ability to interact with HER2, and to prevent its ubiquitination and degradation. Consistently, the overexpression of HSP90-T297A impinges on the viability of HER2-overexpressing cells, further supporting a role of this phosphorylation in the modulation of HER2 tumorigenicity. T297 is located in the middle domain of HSP90, a region that is involved in the interaction of HSP90 with clients. Consistently, structural studies indicate that T297 phosphorylation can indeed favor the chaperone's interaction with HER2, further supporting our hypothesis.

热休克蛋白90 （HSP90）是一种重要的分子伴侣蛋白，其活性不仅受共同伴侣蛋白的调控，还受不同的翻译后修饰的调控。有趣的是，它的伴侣活性对几种癌基因的稳定性至关重要，其中包括受体酪氨酸激酶HER2。HER2在20-30%的乳腺癌和卵巢癌中过度表达。它的过度表达会触发增殖和转化途径的异常激活，因此经常与侵袭性和不良预后特征相关，并与较短的患者生存期相关。值得注意的是，HSP90抑制剂已经在her2阳性乳腺癌中进行了研究，并显示出令人鼓舞的结果。出乎意料的是，我们之前报道了ATM促进HER2与HSP90的相互作用，从而维持HER2蛋白的稳定性和致瘤性。为了进一步研究HER2-HSP90与ATM之间的相互作用，我们验证了ATM可以磷酸化HSP90的假设。我们证实，在HER2阳性乳腺癌模型中，ATM激活可以诱导HSP90的磷酸化。点突变表明，T297是ATM激酶的主要靶向位点，重要的是，不可磷酸化的突变体HSP90-T297A与HER2相互作用的能力降低，并阻止其泛素化和降解。一致地，HSP90-T297A的过表达会影响HER2过表达细胞的生存能力，进一步支持这种磷酸化在调节HER2致瘤性中的作用。T297位于HSP90的中间区域，该区域参与了HSP90与客户端的交互。一致地，结构研究表明T297磷酸化确实有利于伴侣与HER2的相互作用，进一步支持了我们的假设。

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