Biochimica et biophysica acta. Molecular cell research最新文献_第6页

CAT1 modulates hepatic fibrosis via IL-6-mediated inflammatory and fibrogenic pathways in hepatic stellate cells CAT1通过il -6介导的肝星状细胞炎症和纤维化途径调节肝纤维化。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-10-27 DOI: 10.1016/j.bbamcr.2025.120075

Xiaofeng Deng , Zongjuan Li , Zhenyu Xu , Feng Peng

Hepatic fibrosis is characterized by excessive extracellular matrix deposition and chronic inflammation, primarily driven by the activation of hepatic stellate cells (HSCs). The cationic amino acid transporter 1 (CAT1) has been identified as a key regulator of HSCs activation and fibrosis progression, but its interaction with inflammatory pathways remains unclear. This study investigated the role of CAT1 in hepatic fibrosis and its regulatory effect on interleukin-6 (IL-6)-mediated inflammatory and fibrogenic responses. Bioinformatic analysis of published single-cell RNA sequencing data revealed that CAT1 expression was significantly upregulated in activated HSCs and positively correlated with IL-6 levels. Functional assays demonstrated that IL-6 promotes HSCs proliferation, migration, inflammation, and fibrotic marker expression and inhibited apoptosis, while CAT1 knockdown attenuated these effects. IL-6 overexpression reversed the inhibitory effects of CAT1 knockdown on HSCs activation by regulating JAK2/STAT3 signaling pathway, suggesting that IL-6 acts downstream of CAT1 in promoting fibrosis. In vivo, CAT1 knockdown mitigated liver injury, reduced collagen deposition, and suppressed inflammation in both carbon tetrachloride (CCl₄)-induced hepatic fibrosis and non-alcoholic fatty liver disease (NAFLD) models. However, IL-6 overexpression abolished these protective effects, highlighting the CAT1-IL-6 axis as a crucial regulator of liver fibrosis. These findings suggest that targeting CAT1 may provide a novel therapeutic strategy for hepatic fibrosis by modulating IL-6-mediated inflammatory and fibrogenic pathways.

肝纤维化的特征是过度的细胞外基质沉积和慢性炎症，主要由肝星状细胞（hsc）的激活驱动。阳离子氨基酸转运蛋白1 （CAT1）已被确定为造血干细胞活化和纤维化进展的关键调节因子，但其与炎症途径的相互作用尚不清楚。本研究探讨CAT1在肝纤维化中的作用及其对白细胞介素-6 （IL-6）介导的炎症和纤维化反应的调节作用。已发表的单细胞RNA测序数据的生物信息学分析显示，活化的hsc中CAT1表达显著上调，且与IL-6水平呈正相关。功能分析表明，IL-6促进造血干细胞增殖、迁移、炎症和纤维化标志物表达，抑制细胞凋亡，而CAT1的敲除减弱了这些作用。IL-6过表达通过调节JAK2/STAT3信号通路逆转CAT1下调对hsc活化的抑制作用，提示IL-6在CAT1的下游作用促进纤维化。在体内，在四氯化碳（CCl₄）诱导的肝纤维化和非酒精性脂肪性肝病（NAFLD）模型中，CAT1敲低可减轻肝损伤、减少胶原沉积并抑制炎症。然而，IL-6过表达消除了这些保护作用，强调CAT1-IL-6轴是肝纤维化的关键调节因子。这些发现表明，通过调节il -6介导的炎症和纤维化途径，靶向CAT1可能为肝纤维化提供一种新的治疗策略。

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引用次数: 0

Canagliflozin inhibits p38MAPK signaling to protect tubular epithelial cell against pyroptosis in sepsis-induced acute kidney injury 卡格列净抑制p38MAPK信号保护脓毒症诱导的急性肾损伤小管上皮细胞免于焦亡。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-10-12 DOI: 10.1016/j.bbamcr.2025.120069

Yun-feng Zhu , Jing Wang , Rong-xin Bian , Chun-lin Guo , Li-ge Song , Chun-ying Nie , Gang Liu

This paper aimed to investigate the impacts and mechanisms of canagliflozin (CANA) in sepsis-induced acute kidney injury (SAKI). SAKI models were established using HK2 cells treated with lipopolysaccharide (LPS) and mice received cecum ligation puncture (CLP) surgery. The pathological examination was applied to evaluate mouse kidney damage. Inflammatory cytokines were evaluated using ELISA and RT-qPCR assay. Flow cytometry and TUNEL staining were employed to check cell apoptosis. The expression of apoptosis-, inflammation-, pyroptosis-, and pathway-related proteins were assessed via western blot. In CLP-induced mouse SAKI model, CANA attenuated renal pathological injury, inflammation response, pyroptosis and inhibited the p38MAPK pathway, as evidenced by the decrease of serum Scr and BUN levels, cell apoptosis, IL-1β and IL-18 levels, as well as GSDMD-N, cleaved caspase-1, and p38MAPK expression. In HK2 cells treated with LPS, inflammation response, pyroptosis, and the p38MAPK pathway were inhibited by CANA. Moreover, overexpression of p38MAPK reversed CANAs' effects on apoptosis, inflammation response, and pyroptosis in HK2 cells. In SAKI, CANA inhibited the p38MAPK pathway, thereby reducing cell apoptosis, inflammation response, and pyroptosis, which ultimately alleviating disease progression.

本文旨在探讨卡格列净（canagliflozin， CANA）在脓毒症致急性肾损伤（SAKI）中的作用及其机制。采用脂多糖（LPS）处理HK2细胞和盲肠结扎穿刺（CLP）手术小鼠建立SAKI模型。采用病理检查方法评价小鼠肾损害。采用ELISA和RT-qPCR检测炎症因子。流式细胞术和TUNEL染色检测细胞凋亡情况。western blot检测细胞凋亡蛋白、炎症蛋白、焦亡蛋白和通路相关蛋白的表达。在clp诱导的小鼠SAKI模型中，CANA可减轻肾脏病理损伤、炎症反应、焦亡，抑制p38MAPK通路，表现为降低血清Scr和BUN水平、细胞凋亡、IL-1β和IL-18水平，以及GSDMD-N、cleaved caspase-1和p38MAPK表达。在LPS处理的HK2细胞中，CANA抑制了炎症反应、焦亡和p38MAPK通路。此外，p38MAPK的过表达逆转了CANAs对HK2细胞凋亡、炎症反应和焦亡的影响。在SAKI中，CANA抑制p38MAPK通路，从而减少细胞凋亡、炎症反应和焦亡，最终缓解疾病进展。

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引用次数: 0

Cell-penetrant peptides as novel inhibitors of the interaction of coatomer protein COPB2/RACK2 with protein kinase Cε and cargo proteins 细胞渗透肽作为涂层蛋白COPB2/RACK2与蛋白激酶Cε和货物蛋白相互作用的新抑制剂。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-10-18 DOI: 10.1016/j.bbamcr.2025.120071

Abisola A. Olushola-Siedoks , Lewin Small , Kathryn J. Fincham , Dorothy C.C. Wai , Dhruv Monteiro , James R.W. Conway , Antonia Cadell , Benjamin J. Parker , David R. Croucher , Carsten Schmitz-Peiffer , Raymond S. Norton

The lipid-activated novel protein kinase C isoform, PKCε, plays a key role in the progression of Type 2 Diabetes Mellitus (T2DM) and has also been implicated in cancer, cardiac hypertrophy, pain and anxiety. As the spatial regulation of PKCε activity is linked to its interaction with the Receptor for Activated C Kinase 2 (RACK2, also known as COPB2), blockade of this interaction has potential therapeutic benefits for the treatment of several pathologies. Using a proximity-based chemiluminescent assay to monitor the binding of lipid-activated PKCε to RACK2, we discovered inhibitory peptides derived from the PKCε sequence; pentapeptides with a KxKxx motif and a C-terminal carboxylate potently inhibited this interaction, whereas other short sequences containing cationic residues were less effective. An alanine scan of the KIKIC peptide showed that the two Lys residues and C-terminal carboxylate were the most important for inhibitory activity. A previously described PKCε translocation inhibitory peptide from PKCε, εV1-2, exhibited much weaker inhibition of the PKCe-RACK2 interaction, with significant inhibitory activity observed only when it was conjugated to cell-penetrating peptides. KIKIC exhibited moderate cell-penetrating ability, showed no evidence of cytotoxicity, and modified PKCε translocation in response to lipid treatment. Several proteins that were captured in a RACK2 pulldown of a liver lysate in a KIKIC-peptide sensitive manner were identified as part of a PKCε-RACK2 complex isolated from intact cells. These results provide a basis for the rational design of peptides or peptidomimetics that inhibit the PKCε-RACK2 interaction and have potential for the prevention and/or treatment of T2DM.

脂质活化的新型蛋白激酶C异构体PKCε在2型糖尿病（T2DM）的进展中起关键作用，也与癌症、心脏肥厚、疼痛和焦虑有关。由于PKCε活性的空间调控与其与活化C激酶2受体（RACK2，也称为COPB2）的相互作用有关，阻断这种相互作用对治疗多种疾病具有潜在的治疗益处。使用基于接近度的化学发光法来监测脂质活化PKCε与RACK2的结合，我们发现了来自PKCε序列的抑制肽；带有KxKxx基序和c端羧酸的五肽可以有效地抑制这种相互作用，而其他含有阳离子残基的短序列则效果较差。对KIKIC肽的丙氨酸扫描表明，两个赖氨酸残基和c端羧酸是抑制活性最重要的。先前描述的PKCε易位抑制肽，εV1-2，对PKCe-RACK2相互作用的抑制作用要弱得多，只有当它与细胞穿透肽结合时才有显著的抑制活性。KIKIC表现出中等的细胞穿透能力，没有细胞毒性，并在脂质处理下改变pkce ε易位。以kikic肽敏感的方式在肝裂解物的RACK2下拉中捕获的几个蛋白被鉴定为从完整细胞中分离的PKCε-RACK2复合体的一部分。这些结果为合理设计抑制PKCε-RACK2相互作用的肽或肽拟物提供了基础，并具有预防和/或治疗T2DM的潜力。

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引用次数: 0

Hotspot mutant p53-R273H enhances mitochondrial biogenesis and cell migration in primary colorectal cancer in response to oxaliplatin 热点突变体p53-R273H对奥沙利铂的响应增强了原发性结直肠癌的线粒体生物发生和细胞迁移。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-10-27 DOI: 10.1016/j.bbamcr.2025.120073

Toni Martinez-Bernabe , Pere Miquel Morla-Barcelo , Alessandra Fiore , Massimo Donadelli , Pilar Roca , Jordi Oliver , Jorge Sastre-Serra , Daniel G. Pons

Oxaliplatin is commonly known as a successful chemotherapy for advanced colorectal cancer, improving patient survival and eradicating micro-metastases, but its use in early stages remains controversial. Mitochondria fuel energy-intensive programs such as cell migration, yet how oxaliplatin regulates the mitochondrial network in CRC - and how TP53 context shapes this - remains unclear. We investigated a matched pair of CRC cell lines from the same patient - SW480 (primary) and SW620 (lymph-node metastasis) - both harboring TP53-R273H mutation, to define differential responses in mitochondrial biogenesis, dynamics and respiration and the mechanisms underlying them. The results indicate that primary-derived colorectal cancer cell line increased cell migration, mitochondrial biogenesis, and mitochondrial respiration capacity in response to oxaliplatin through a new and firstly described gain-of-function (GOF) of p53-R273H. Additionally, in the primary-derived CRC line, oxaliplatin elicited fate heterogeneity - coexisting apoptotic and senescent fractions alongside an R273H-driven, bioenergetically primed migratory subpopulation - together with increased mitochondrial biogenesis and respiratory capacity; by contrast, the metastatic-derived line was more sensitive and displayed structural mitochondrial injury with reduced maximal respiration. More broadly, this work underscores the importance of p53 gain-of-function mutations in CRC: the same GOF (TP53-R273H) amplifies cell migration by coupling an enhanced mitochondrial biogenesis/OXPHOS program to motility. Oxaliplatin further accentuates this energetically primed, pre-metastatic state, arguing for mitochondrial-targeted combination strategies in early-stage CRC.

奥沙利铂通常被认为是一种成功的晚期结直肠癌化疗药物，可以提高患者的生存率并根除微转移，但在早期阶段使用奥沙利铂仍存在争议。线粒体为细胞迁移等能量密集型程序提供燃料，但奥沙利铂如何调节结直肠癌中的线粒体网络，以及TP53环境如何影响线粒体网络，目前尚不清楚。我们研究了来自同一患者的一对匹配的CRC细胞系- SW480（原发）和SW620（淋巴结转移）-都携带TP53-R273H突变，以确定线粒体生物发生，动力学和呼吸的差异反应及其潜在机制。结果表明，原发结直肠癌细胞系通过p53-R273H的新功能获得（GOF），增加了奥沙利铂对细胞迁移、线粒体生物发生和线粒体呼吸能力的反应。此外，在原发CRC细胞系中，奥沙利铂引发了命运异质性——与r273h驱动的、生物能量启动的迁移亚群共存的凋亡和衰老部分，以及线粒体生物发生和呼吸能力的增加；相比之下，转移源系更敏感，表现出结构性线粒体损伤，最大呼吸减少。更广泛地说，这项工作强调了p53功能获得突变在结直肠癌中的重要性：相同的GOF （TP53-R273H）通过将增强的线粒体生物发生/OXPHOS程序与运动性耦合来放大细胞迁移。奥沙利铂进一步强化了这种能量启动的前转移状态，主张在早期CRC中采用线粒体靶向联合策略。

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引用次数: 0

ATR-FTIR spectroscopy as a reliable analytical tool in cancer research: Tracking glycosylation-induced protein and lipid alteration in extracellular vesicles ATR-FTIR光谱在癌症研究中的可靠分析工具：追踪细胞外囊泡中糖基化诱导的蛋白质和脂质改变。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-11-04 DOI: 10.1016/j.bbamcr.2025.120082

Magdalena Wilczak , Andrzej Wróbel , Magdalena Surman , Martyna Durak-Kozica , Ewa Ł. Stępień , Małgorzata Przybyło

The rising incidence of cancer creates an urgent need to develop faster methods for early detection. Fourier Transform Infrared Spectroscopy (FTIR) spectroscopy is a promising technique to analyse molecular content in biological samples. FTIR has also been used to study structural changes in extracellular vesicles (EVs), revealing alterations in protein secondary structure, protein-to-lipid ratio, and protein phosphorylation levels. We investigated how changes in glycosylation, which naturally occur during tumor progression, affect the previously mentioned parameters and whether these cellular changes are reflected in EV composition. The WM266–4 melanoma cell line, treated with two glycosylation inhibitors, was used as a model. After treatment, EVs were isolated and ATR-FTIR measurements were performed, followed by a comprehensive analysis of the data. Significant differences in protein and lipid content were observed between EV populations treated with glycosylation inhibitors, with greater changes in EVs compared to cells. Glycosylation inhibitors also increased the level of phosphorylated proteins in EVs. Our findings showed that changes in EVs were more dynamic than at the cellular level cells. The presented analysis shows that subtle molecular changes can significantly impact EV cargo and properties. FTIR is a powerful tool for detecting these changes and may aid future cancer diagnostics.

癌症发病率不断上升，迫切需要开发更快的早期检测方法。傅里叶变换红外光谱（FTIR）是一种很有前途的分析生物样品中分子含量的技术。FTIR也被用于研究细胞外囊泡（EVs）的结构变化，揭示蛋白质二级结构、蛋白脂比和蛋白质磷酸化水平的变化。我们研究了在肿瘤进展过程中自然发生的糖基化变化如何影响上述参数，以及这些细胞变化是否反映在EV组成中。用两种糖基化抑制剂处理的WM266-4黑色素瘤细胞系作为模型。治疗后，分离EVs，进行ATR-FTIR测量，然后对数据进行综合分析。在糖基化抑制剂处理的EV群体之间，观察到蛋白质和脂质含量的显著差异，与细胞相比，EV的变化更大。糖基化抑制剂也增加了ev中磷酸化蛋白的水平。我们的研究结果表明，电动汽车的变化比细胞水平的变化更具动态性。分析表明，微小的分子变化会显著影响电动汽车的载货量和性能。FTIR是检测这些变化的有力工具，可能有助于未来的癌症诊断。

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引用次数: 0

Macrophage-derived FN1 promotes peritoneal cavity metastasis of gastric cancer by inhibiting the Hippo signaling pathway via SDC4 巨噬细胞来源的FN1通过SDC4抑制Hippo信号通路促进胃癌腹腔转移。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-09-24 DOI: 10.1016/j.bbamcr.2025.120063

Meixia Zhang, Mingyan He, Fan Du, Yingping Xie, Ye Liao, Xiaolin Pan

Gastric cancer (GC) is a prevalent malignant tumor worldwide. Peritoneal cavity metastasis is recognized as a critical clinical feature of late-stage GC. Fibronectin 1 (FN1) is closely associated with the development and progression of various cancers. This study aimed to investigate the functions of FN1 and the underlying mechanisms in peritoneal cavity metastasis of GC. A bioinformatics reanalysis of the single-cell sequencing dataset GSE140182 was performed to explore the cellular signature in malignant ascites. Cell communication analysis was performed to identify the cell communication between macrophages and tumor cells. GC cells were cultured with supernatant from FN1-overexpressing macrophages to investigate the effects and potential mechanism of FN1 action on GC cells by Western blot (WB) assay, MTT assay, migration and invasion assay, clone formation assay, cell adhesion assay, and functional rescue experiments. To further validate the impact of FN1 on GC and its peritoneal cavity metastasis were carried out in vivo experiments. Cellular communication between macrophages and GC cells was mediated by FN1-SDC4. Overexpression of macrophage-derived FN1 facilitated the malignant phenotypes of GC cells and the peritoneal cavity metastasis of GC in vivo. Mechanistically, macrophage-derived FN1 inhibited the Hippo signaling pathway by enhancing the expression of SDC4 in GC cells. Knockdown of SDC4 reversed the tumor-promoting effects induced by macrophage-derived FN1. Our study revealed that macrophage-derived FN1 inhibited the Hippo signaling pathway by upregulating the expression of SDC4 in GC cells, thereby promoting peritoneal cavity metastasis of GC.

胃癌是世界范围内常见的恶性肿瘤。腹膜腔转移被认为是晚期胃癌的一个重要临床特征。纤维连接蛋白1 （FN1）与多种癌症的发生和发展密切相关。本研究旨在探讨FN1在胃癌腹腔转移中的作用及其机制。对单细胞测序数据集GSE140182进行生物信息学再分析，以探索恶性腹水的细胞特征。通过细胞通讯分析，确定巨噬细胞与肿瘤细胞之间的细胞通讯。用过表达FN1的巨噬细胞上清液培养GC细胞，通过WB法、MTT法、迁移侵袭法、克隆形成法、细胞粘附法和功能拯救实验研究FN1对GC细胞的作用及其可能机制。为了进一步验证FN1对胃癌及其腹腔转移的影响，我们进行了体内实验。巨噬细胞与GC细胞之间的细胞通讯是由FN1-SDC4介导的。巨噬细胞源性FN1的过表达促进了胃癌细胞的恶性表型和胃癌在体内的腹腔转移。在机制上，巨噬细胞来源的FN1通过增强GC细胞中SDC4的表达来抑制Hippo信号通路。敲低SDC4可逆转巨噬细胞源性FN1诱导的促肿瘤作用。我们的研究发现，巨噬细胞来源的FN1通过上调GC细胞中SDC4的表达抑制Hippo信号通路，从而促进GC的腹腔转移。

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引用次数: 0

COA6 deficiency inhibits hepatocellular carcinoma progression by regulating cuproptosis through the JAK/STAT signaling pathway COA6缺乏通过JAK/STAT信号通路调节cuprotic抑制肝细胞癌进展。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-09-25 DOI: 10.1016/j.bbamcr.2025.120065

Kailiang Tian , Yang Yang , Xiaohang Niu , Xiaoming Wei , Mingjin Zhang , Yangliu Zhou , Mingya Yang , Haonan Sun , Lixin Zhu , Fubao Liu

Background

Hepatocellular carcinoma (HCC) is one of the most common and deadly malignant tumors with limited therapeutic strategies. COA6 is a mitochondria-associated protein that plays an important role in regulating tumor cuproptosis, but its role in HCC is currently unknown. In this study, we aimed to investigate the expression and potential mechanism of action of COA6 in HCC.

Methods

TCGA-LIHC database was analyzed for differentially expressed cuproptosis-related genes (CRGs) in HCC and prognostic value, which was validated by immunohistochemistry and Western blot. CCK8, flow cytometry, wound healing, transwell and subcutaneous graft tumor assays were performed to explore the function of COA6 in HCC. Impact of COA6 on cuproptosis was assessed by assay kit and Western blot. RNA-sequencing were used to determine molecular mechanism. Immunoprecipitation (Co-IP) and immunofluorescence were used to assess the relationship between COA6 and NDUFA4L2. western blotting was used to detect the effect of COA6 on the JAK-STAT pathway.

Results

COA6 was significantly overexpressed in HCC tissues and HCC cell lines and was closely associated with poor prognosis. Silencing COA6 significantly inhibited the malignant phenotype of HUH7 and HepG2 cells in vitro and tumor growth in vivo. Moreover, silencing COA6 promoted ROS accumulation and activated cuproptosis in HCC cells. Interestingly, we found that COA6 interacted with NDUFA4L2 and COA6 deficiency significantly inhibited the JAK-STAT signaling pathway.

Conclusions

In conclusion, our data show that COA6 was highly expressed in HCC, and silencing COA6 blocked the JAK-STAT signaling pathway and activated cuproptosis, and inhibits the malignant phenotype and tumor growth of HCC cells. Therefore, targeting COA6 may be a potential therapeutic approach to inhibit HCC progression.

背景：肝细胞癌（HCC）是最常见、最致命的恶性肿瘤之一，治疗策略有限。COA6是一种线粒体相关蛋白，在调节肿瘤铜质增生中起重要作用，但其在HCC中的作用目前尚不清楚。本研究旨在探讨COA6在HCC中的表达及其潜在的作用机制。方法：分析TCGA-LIHC数据库中cuprotosis相关基因（CRGs）在HCC中的差异表达及其预后价值，并通过免疫组化和Western blot验证。CCK8、流式细胞术、创面愈合、经井及皮下移植肿瘤检测探讨COA6在HCC中的功能。采用检测试剂盒和Western blot检测COA6对铜生长的影响。采用rna测序法确定其分子机制。采用免疫沉淀法（Co-IP）和免疫荧光法评估COA6与NDUFA4L2之间的关系。western blotting检测COA6对JAK-STAT通路的影响。结果：COA6在HCC组织和HCC细胞系中显著过表达，并与预后不良密切相关。沉默COA6可显著抑制HUH7和HepG2细胞的体外恶性表型和体内肿瘤生长。此外，在HCC细胞中，沉默COA6可促进ROS积累并激活cuproosis。有趣的是，我们发现COA6与NDUFA4L2相互作用，COA6缺乏显著抑制了JAK-STAT信号通路。结论：综上所述，我们的数据表明，COA6在HCC中高表达，沉默COA6可阻断JAK-STAT信号通路，激活cuprotosis，抑制HCC细胞的恶性表型和肿瘤生长。因此，靶向COA6可能是抑制HCC进展的潜在治疗方法。

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引用次数: 0

Glaucoma-associated polymorphism M98K-OPTN sensitizes retinal cells to protein homeostasis stress through p62-mediated caspase activation 青光眼相关多态性M98K-OPTN通过p62介导的caspase激活使视网膜细胞对蛋白稳态应激敏感

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-09-24 DOI: 10.1016/j.bbamcr.2025.120064

Swetha Medchalmi, Zuberwasim Sayyad , Ghanshyam Swarup

M98K polymorphism of OPTN is significantly associated with glaucoma in certain populations. This raises the possibility that M98K-OPTN alone is not sufficient to cause glaucoma, and it may require cooperation with other genetic or environmental factors to induce glaucoma. Loss of vision in glaucoma occurs due to the degeneration of retinal ganglion cells. Here, we have tested the hypothesis that M98K-OPTN may enhance the sensitivity of retinal cells to protein homeostasis stress. For this purpose, we have used M98K-OPTN expressing and wild-type (WT)-OPTN expressing clones of retinal 661W cells. Upon induction of protein homeostasis stress by a proteasome inhibitor MG132 (1–2 μM), M98K-OPTN expressing cells showed reduced survival, and enhanced caspase-8, caspase-9, and caspase-3 activation in comparison with WT-OPTN expressing cells. Compared to WT-OPTN expressing cells, M98K-OPTN expressing cells showed enhanced formation of p62/SQSTM1-positive aggregates and enhanced p62 protein level under conditions of protein homeostasis stress. Knockdown of p62 resulted in reduced caspase-9, caspase-8, and caspase-3 activation in M98K-OPTN expressing cells treated with proteasome inhibitor. Our results suggest that M98K-OPTN modulates protein homeostasis stress-induced signalling that mediates p62-dependent caspase activation, which leads to enhanced sensitivity of M98K-OPTN expressing retinal cells to protein homeostasis stress.

在某些人群中，OPTN的M98K多态性与青光眼显著相关。这就提出了单独M98K-OPTN不足以引起青光眼的可能性，可能需要与其他遗传或环境因素共同作用才能诱发青光眼。青光眼的视力丧失是由于视网膜神经节细胞的退化。在这里，我们测试了M98K-OPTN可能增强视网膜细胞对蛋白质稳态应激的敏感性的假设。为此，我们使用了表达M98K-OPTN和野生型(WT)-OPTN的视网膜661W细胞克隆。蛋白酶体抑制剂MG132 （1-2 μM）诱导蛋白稳态应激后，与WT-OPTN表达细胞相比，表达M98K-OPTN的细胞存活率降低，caspase-8、caspase-9和caspase-3活性增强。与WT-OPTN表达细胞相比，M98K-OPTN表达细胞在蛋白稳态胁迫条件下p62/ sqstm1阳性聚集体的形成增强，p62蛋白水平升高。p62的敲低导致M98K-OPTN表达细胞中caspase-9、caspase-8和caspase-3活性降低。我们的研究结果表明，M98K-OPTN调节蛋白稳态应激诱导的信号，介导p62依赖性caspase激活，从而导致表达M98K-OPTN的视网膜细胞对蛋白稳态应激的敏感性增强。

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引用次数: 0

Transgenic overexpression of miR-486 and sAnk1.5 does not alter glucose handling in mice 转基因过表达miR-486和sAnk1.5不会改变小鼠的葡萄糖处理。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-11-17 DOI: 10.1016/j.bbamcr.2025.120087

S. Buonocore , F. Fiore , E.M. Rubino , M.R. Catallo , L. Raucci , A. Laurino , D. Rossi , E. Pierantozzi , V. Sorrentino

Recent studies have shown that the C allele of SNP rs508419 is associated with susceptibility to Type 2 diabetes (T2D). This SNP lies within the muscle-specific P2 promoter of human ANK1, which drives transcription of the sAnk1.5 isoform and miR-486. The C allele increases P2 promoter activity, resulting to higher levels of sAnk1.5 transcript and protein in striated muscles.

We now present the first evidence that in skeletal muscle of individuals homozygous for the rs508419 C allele, also the hsa-miR-486-5p is transcribed at higher levels. This raises the question of whether T2D susceptibility may be associated with simultaneous overexpression of miR-486-5p and sAnk1.5. To test this hypothesis, we generated and characterized double transgenic (D-Tg) mice that selectively overexpress both mmu-miR-486-5p and sAnk1.5 in skeletal muscle tissue.

Analysis of sAnk1.5 and miR-486-5p expression in D-Tg mouse showed that despite both transgenes were significantly upregulated, a discrepancy between sAnk1.5 mRNA and protein levels was observed, suggesting that sAnk1.5 protein levels are further regulated by post-translational mechanism. D-Tg mice were monitored from 2 to 12 months of age to assess body weight, fat and lean mass, blood glucose levels under fasting conditions, as well as during intraperitoneal glucose tolerance tests and insulin tolerance tests, performed under either standard or high fat diet conditions. No differences were observed between D-Tg and age-matched wild type control mice for any of the parameters tested, indicating that the link between rs508419 and susceptibility to T2D cannot be ascribed to increased expression of miR-486-5p and sAnk1.5 in skeletal muscle.

最近的研究表明SNP rs508419的C等位基因与2型糖尿病（T2D）易感性相关。该SNP位于人类ANK1的肌肉特异性P2启动子内，其驱动sAnk1.5亚型和miR-486的转录。C等位基因增加P2启动子活性，导致横纹肌中sAnk1.5转录物和蛋白水平升高。我们现在提出了第一个证据，即在rs508419 C等位基因纯合的个体的骨骼肌中，hsa-miR-486-5p的转录水平也更高。这就提出了T2D易感性是否可能与miR-486-5p和sAnk1.5同时过表达有关的问题。为了验证这一假设，我们产生并表征了双转基因（D-Tg）小鼠，这些小鼠在骨骼肌组织中选择性地过表达mmu-miR-486-5p和sAnk1.5。对D-Tg小鼠中sAnk1.5和miR-486-5p表达的分析显示，尽管两种转基因均显著上调，但sAnk1.5 mRNA和蛋白水平存在差异，表明sAnk1.5蛋白水平进一步受到翻译后机制的调控。D-Tg小鼠在2至12 月龄期间进行监测，以评估空腹条件下的体重、脂肪和瘦质量、血糖水平，以及在标准或高脂肪饮食条件下进行的腹腔葡萄糖耐量试验和胰岛素耐量试验。在D-Tg和年龄匹配的野生型对照小鼠之间，没有观察到任何参数的差异，这表明rs508419与T2D易感性之间的联系不能归因于骨骼肌中miR-486-5p和sAnk1.5的表达增加。

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引用次数: 0

Plasma membrane Bile acid TGR5 receptor specific stimulation induces Ca2+ mobilisation, ATP secretion and P2Y receptors activation in cholangiocytes 质膜胆汁酸TGR5受体特异性刺激诱导胆管细胞Ca2+动员、ATP分泌和P2Y受体激活。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2026-01-01 Epub Date: 2025-09-30 DOI: 10.1016/j.bbamcr.2025.120067

Xuanmeng Chen , Amr Al-Shebel , Thibault Pebrier , Thierry Tordjmann , Olivier Dellis

The Bile Acid receptor TGR5 is well known to activate the cAMP pathway leading to CFTR activation and Cl⁻ ions secretion, needed for bile alkalinization and hydration. However, during cystic fibrosis development, only 10 to 15 % of the patients present liver defects due to bile duct disorders, meaning that another process should compensate for the loss of CFTR activity. Interestingly, some bile acids had also been reported to mobilize Ca²⁺ ions in cholangiocytes. Using normal human cholangiocytes and cholangiocarcinoma cell lines, we confirmed by using a specific agonist, that TGR5 stimulation induced a Ca²⁺ release from the endoplasmic reticulum and an influx of extracellular Ca²⁺ ions. Next, this Ca²⁺ mobilisation allows an ATP (and UTP) release, leading to the activation of P2Y receptors, reinforcing this Ca²⁺ mobilisation. This study shows that activation of the BA receptor TGR5 has the capacity to induce the two main intracellular pathways, cAMP and IP₃-Ca²⁺ in cholangiocytes. From our data, we speculate that the pathway we described will allow activation of the Ca²⁺-activated Cl⁻ channels TMEM16A, to compensate in part or in totality the loss of CFTR in CF patients.

众所周知，胆汁酸受体TGR5可激活cAMP通路，导致CFTR激活和胆汁碱化和水化所需的Cl-离子分泌。然而，在囊性纤维化的发展过程中，只有10%至15% %的患者由于胆管疾病而出现肝脏缺陷，这意味着另一个过程应该补偿CFTR活性的丧失。有趣的是，一些胆汁酸也被报道在胆管细胞中调动Ca2+离子。使用正常的人类胆管细胞和胆管癌细胞系，我们通过使用一种特定的激动剂证实，TGR5刺激诱导Ca2+从内质网释放和细胞外Ca2+离子的流入。接下来，这种Ca2+动员允许ATP（和UTP）释放，导致P2Y受体的激活，加强这种Ca2+动员。本研究表明，BA受体TGR5的激活具有诱导胆管细胞内cAMP和IP3-Ca2+两种主要细胞内通路的能力。根据我们的数据，我们推测我们描述的途径将允许激活Ca2+激活的Cl-通道TMEM16A，以部分或全部补偿CF患者CFTR的损失。

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引用次数: 0