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

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 : 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 : 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

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 : 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

Corrigendum to “Inhibition of autophagy sensitises cells to hydrogen peroxide-induced apoptosis: Protective effect of mild thermotolerance acquired at 40 °C” [Biochim. Biophys. Acta Mol. Cell Res. (2016) volume 1863(12) 3050-3064 / PMID: 27666506] “抑制自噬使细胞对过氧化氢诱导的凋亡敏感：在40°C下获得的轻度耐热性的保护作用”[biochem]的更正。Biophys。Acta Mol Cell Res. (2016) volume 1863(12) 3050-3064 / PMID: 27666506]。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-19 DOI: 10.1016/j.bbamcr.2025.120061

M. Redza-Dutordoir, S. Kassis, H. Ve, M. Grondin, D.A. Averill-Bates

引用次数: 0

RIPK3 activation promotes peritoneal dialysis-related peritoneal fibrosis via NLRP3/Caspase-1/IL-1β pathway RIPK3激活通过NLRP3/Caspase-1/IL-1β途径促进腹膜透析相关的腹膜纤维化。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-13 DOI: 10.1016/j.bbamcr.2025.120060

Zhiyong Xie , Rong Wei , Wenying Zhang , Xiaodong Tang , Hang Chen , Qilan Nie , Xinying Zhang , Yilin Chen , Zhuohan Li , Ziqing Tan , Minwei Du , Yuyao Zhang , Xuan Peng , Hui Di , Yueqiang Wen , Ying Huang , Long Xiao , Jianbo Liang , Dezhu Chen , Zebin Wang , Ying Zhang

Peritoneal fibrosis is one of the leading causes for withdraw of peritoneal dialysis (PD) but there is no available effective therapy strategy. As an essential role in regulating TNF-induced necroptosis, receptor interacting protein kinase-3 (RIPK3) participated in the progression of multiple organ fibrosis. Here, we investigated the role and the possible mechanism of RIPK3 in PD-associated peritoneal fibrosis in PD patients, a mouse peritoneal dialysis model and in vitro peritoneal mesothelial cells. We found that phosphorylated-RIPK3 (p-RIPK3) were markedly elevated in PD fluids and peritoneal tissue from PD patients, a mouse PD model and in peritoneal mesothelial cells induced by TGFβ and high glucose PD fluids. And activated RIPK3 recruits its substrate protein, MLKL, and promotes its phosphorylation. RIPK3 kinase inhibition using GSK’872 compound could attenuate high glucose PD fluid-induced peritoneal fibrosis in a mouse PD model. In vitro peritoneal mesothelial cells, RIPK3 kinase inhibition or siRNA transfection target on RIPK3 attenuate TGFβ or high glucose PD fluid-induced fibrotic progress. Meanwhile, GSK’872 intervention could inhibit the NLRP3/Caspase-1/IL-1β pathway in PD mouse model and in vitro peritoneal mesothelial cells, inhibiting RIPK3 kinase activity or siRNA silencing RIPK3 expression could block NLRP3/Caspase-1/IL-1β pathway. Moreover, Co-immunoprecipitation (Co-IP) experiment and immunofluorescence indicated that p-RIPK3 could combinate with NLRP3 and TGFβ intervention could promote this interaction, while RIPK3 kinase inhibitor could avianize their combination. These findings implicate that RIPK3 activation may be a crucial mediator in PD associated peritoneal fibrosis and targeting RIPK3 activation may be a novel therapeutic strategy to attenuate PD-related peritoneal fibrosis.

腹膜纤维化是腹膜透析（PD）退出的主要原因之一，但目前还没有有效的治疗策略。受体相互作用蛋白激酶3 （receptor interacting protein kinase-3, RIPK3）在调节tnf诱导的坏死性坏死中起重要作用，参与了多器官纤维化的进展。在这里，我们研究了RIPK3在PD患者、小鼠腹膜透析模型和体外腹膜间皮细胞中PD相关腹膜纤维化的作用和可能的机制。我们发现磷酸化ripk3 （p-RIPK3）在PD患者、小鼠PD模型的PD液和腹膜组织以及TGFβ和高糖PD液诱导的腹膜间皮细胞中显著升高。激活的RIPK3招募其底物蛋白MLKL，并促进其磷酸化。使用GSK'872化合物抑制RIPK3激酶可减轻高糖PD液诱导的小鼠PD模型腹膜纤维化。在体外腹膜间皮细胞中，RIPK3激酶抑制或siRNA转染靶向RIPK3可减弱TGFβ或高糖PD液诱导的纤维化进展。同时，GSK'872干预可抑制PD小鼠模型及体外腹膜间皮细胞NLRP3/Caspase-1/IL-1β通路，抑制RIPK3激酶活性或siRNA沉默RIPK3表达可阻断NLRP3/Caspase-1/IL-1β通路。此外，共免疫沉淀（Co-IP）实验和免疫荧光实验表明，p-RIPK3可以与NLRP3结合，TGFβ干预可以促进这种相互作用，而RIPK3激酶抑制剂可以使它们的结合无鸟化。这些发现表明，RIPK3激活可能是PD相关腹膜纤维化的关键介质，靶向RIPK3激活可能是减轻PD相关腹膜纤维化的一种新的治疗策略。

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引用次数: 0

SYK overexpression enhances microtubule instability in an MDA-MB-231-derived paclitaxel-resistant cell line 在mda - mb -231衍生的紫杉醇耐药细胞系中，SYK过表达增强微管不稳定性。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-08 DOI: 10.1016/j.bbamcr.2025.120059

Hsiao-Hui Kuo, Chien-Wei Huang, Wei-Rou Chiang, Chieh-Ting Fang, Shang-Yuan Liu, Ling-Huei Yih

Paclitaxel resistance is a major obstacle to achieving long-term remission in patients with triple-negative breast cancer (TNBC), and effective strategies to overcome drug resistance would have significant clinical impact. In this study, we established a paclitaxel-resistant cell clone, T50R, from the human TNBC cell line MDA-MD-231. Intriguingly, these drug-resistant T50R cells required paclitaxel for proliferation. When cultured in the absence of drug, the cells exhibited high dynamic instability of microtubules (MTs) and spindle abnormalities, causing their accumulation in mitosis phase and cell death. Thus, the increased instability of MTs in T50R cells may contribute to the drug requirement for cell growth and drug-resistant phenotype, as paclitaxel counteracts the effect. Compared to the parental MDA-MD-231 cells, T50R cells had elevated expression of spleen tyrosine kinase (SYK), and inhibition or depletion of SYK in the T50R cells cultured without paclitaxel restored MT stability, reduced spindle defects and rescued cell death, suggesting that SYK overexpression contributes to the enhanced MT instability in T50R cells. Furthermore, T50R cells exhibited signs of ER stress and underwent ferroptotic cell death when cultured without paclitaxel, both of which could be ameliorated by inhibition of SYK. Finally, small molecules that target SYK or induce ferroptosis could significantly enhance T50R cell sensitivity to paclitaxel. Together, our results show that SYK-enhanced MT dynamic instability can play an important role in paclitaxel resistance and that targeting the SYK pathway may enhance paclitaxel response.

紫杉醇耐药是三阴性乳腺癌（TNBC）患者实现长期缓解的主要障碍，克服耐药的有效策略将具有重大的临床影响。在这项研究中，我们从人TNBC细胞系MDA-MD-231中建立了紫杉醇耐药细胞克隆T50R。有趣的是，这些耐药T50R细胞需要紫杉醇才能增殖。在没有药物的情况下，细胞表现出微管（mt）的高度动态不稳定性和纺锤体异常，导致它们在有丝分裂期积聚和细胞死亡。因此，T50R细胞中MTs不稳定性的增加可能有助于细胞生长和耐药表型的药物需求，因为紫杉醇抵消了这种作用。与亲代MDA-MD-231细胞相比，T50R细胞中脾脏酪氨酸激酶（SYK）的表达升高，不含紫杉醇培养的T50R细胞中SYK的抑制或缺失恢复了MT的稳定性，减少了纺锤体缺陷，挽救了细胞死亡，表明SYK的过表达导致了T50R细胞MT的不稳定性增强。此外，在不添加紫杉醇的情况下，T50R细胞表现出内质网应激的迹象，并发生铁致细胞死亡，这两种情况都可以通过抑制SYK来改善。最后，靶向SYK或诱导铁下垂的小分子可显著增强T50R细胞对紫杉醇的敏感性。综上所述，我们的研究结果表明SYK增强的MT动态不稳定性在紫杉醇耐药中起重要作用，靶向SYK通路可能增强紫杉醇应答。

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引用次数: 0

Knockdown of translocon-associated protein subunit beta (TRAPβ) stimulates cell cycle arrest and apoptosis in human colorectal cancer cells trans - locon-associated protein subunit β (TRAPβ)的敲低刺激人类结直肠癌细胞的细胞周期阻滞和凋亡。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-07 DOI: 10.1016/j.bbamcr.2025.120057

Darshika Amarakoon, Jing Peng, Cheng-I Wei, Seong-Ho Lee

Translocon-associated protein subunit beta (TRAPβ), also known as signal sequence receptor 2 (SSR2) serves as an auxiliary protein facilitating co-translational translocation in the endoplasmic reticulum (ER); however, its role in colorectal cancer is unknown to date. The objectives of the current study are to examine if TRAPβ/SSR2 knockdown affects the cell proliferation and to elucidate mechanisms by which TRAPβ/SSR2 regulates proliferation of human colorectal cancer. We silenced TRAPβ/SSR2 transiently and stably in human colorectal cancer cell lines and analyzed cell proliferative properties. Transient transfection of TRAPβ/SSR2 siRNA significantly repressed the viability of five different types of human colorectal cancer cells. Flow cytometry and western blot showed that TRAPβ/SSR2 knockdown led to significant increase of G2/M-phase arrest in SW480 cells and S-phase arrest in HCT116 and DLD-1 cells. Annexin V-fluorescein isothiocyanate and propidium iodide staining showed that TRAPβ/SSR2 knockdown significantly induced apoptosis in SW480, HCT116, and DLD-1 cells. Similarly, SW480 stable cells with TRAPβ/SSR2 knockdown showed a significant inhibition of anchorage-independent cell growth, an increase of G2/M-phase arrest with downregulation of cyclin B1, and increase of apoptosis. Regarding mechanisms, TRAPβ/SSR2 knockdown mitigated epidermal growth factor-stimulated activation of mitogen-activated protein kinase (MAPK) pathways and showed significantly decreased expression of inositol-requiring enzyme 1 alpha (IRE1α), while IRE1α reintroduction in TRAPβ/SSR2 knockdown cells reversed G2/M-phase arrest and promoted cell cycle progression. All taken together, our data demonstrate that TRAPβ/SSR2 in the ER could be a molecular target to control cell cycle progression and apoptosis through MAPK-mediated and IRE1α-mediated pathways in human colorectal cancer cells.

trans - loon -associated protein subunit β (TRAPβ)，也被称为信号序列受体2 (SSR2)，是一种辅助蛋白，促进内质网（ER）的共翻译易位；然而，它在结直肠癌中的作用至今尚不清楚。本研究的目的是检查TRAPβ/SSR2敲低是否影响细胞增殖，并阐明TRAPβ/SSR2调节人类结直肠癌增殖的机制。我们在人类结直肠癌细胞系中短暂稳定地沉默TRAPβ/SSR2，并分析细胞增殖特性。瞬时转染TRAPβ/SSR2 siRNA可显著抑制五种不同类型人结直肠癌细胞的活力。流式细胞术和western blot结果显示，TRAPβ/SSR2基因敲低导致SW480细胞的G2/ m期阻滞和HCT116和DLD-1细胞的s期阻滞显著增加。Annexin v -异硫氰酸荧光素和碘化丙啶染色显示，TRAPβ/SSR2敲低显著诱导SW480、HCT116和DLD-1细胞凋亡。同样，敲低TRAPβ/SSR2的SW480稳定细胞显示出锚定不依赖细胞生长的显著抑制，G2/ m期阻滞增加，cyclin B1下调，凋亡增加。机制方面，TRAPβ/SSR2敲低可减轻表皮生长因子刺激的有丝分裂原活化蛋白激酶（MAPK）通路的激活，并显著降低肌醇需要酶1α (IRE1α)的表达，而IRE1α在TRAPβ/SSR2敲低细胞中的重新引入逆转了G2/ m期阻滞，促进了细胞周期的进展。综上所述，我们的数据表明，内质网中的TRAPβ/SSR2可能是通过mapk介导和ire1 α介导的途径控制人类结直肠癌细胞周期进程和凋亡的分子靶点。

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引用次数: 0

GJB2 promotes ovarian cancer progression and cisplatin resistance by upregulating TNC expression GJB2通过上调TNC表达促进卵巢癌进展和顺铂耐药。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-05 DOI: 10.1016/j.bbamcr.2025.120058

Jiaxuan Zhao , Yunfei Lu , Kun Yang , Linfeng Zhou , Haoran Fu , Yingying Sai , Jinghua Wu

Cisplatin resistance continues to be a major obstacle in the treatment of ovarian cancer (OC). Gap junction protein β-2 (GJB2), a key member of the connexin family, is well-known for its association with hereditary deafness. However, its role in ovarian cancer chemotherapy resistance remains unexplored. In this study, we found that increased expression of GJB2 was observed in OC patients with poor prognosis and in cisplatin-resistant OC cells. GJB2 knockdown in OVCAR-3 cells inhibited cancer progression and enhanced cisplatin sensitivity via increased drug uptake, while GJB2 overexpression promoted tumor progression and cisplatin resistance. Furthermore, a positive correlation between GJB2 and TNC expression was identified in clinical tissue samples. TNC knockdown in GJB2-overexpressing cells eliminated GJB2-driven OC progression and cisplatin resistance. Finally, epicatechin enhanced drug uptake mediated cisplatin sensitivity by inhibiting the GJB2 expression. This study demonstrates that GJB2 is a potential therapeutic target for overcoming cisplatin resistance in OC by upregulating TNC expression. Epicatechin may enhance cisplatin efficacy by targeting GJB2.

顺铂耐药仍然是卵巢癌（OC）治疗的主要障碍。间隙连接蛋白β-2 （GJB2）是连接蛋白家族的关键成员，因其与遗传性耳聋有关而闻名。然而，它在卵巢癌化疗耐药中的作用仍未被探索。在本研究中，我们发现GJB2在预后不良的OC患者和顺铂耐药OC细胞中表达升高。GJB2敲低OVCAR-3细胞抑制肿瘤进展，通过增加药物摄入增强顺铂敏感性，而GJB2过表达促进肿瘤进展和顺铂耐药。此外，在临床组织样本中发现GJB2与TNC表达呈正相关。gjb2过表达细胞中TNC的下调消除了gjb2驱动的OC进展和顺铂耐药。最后，表儿茶素通过抑制GJB2表达增强药物摄取介导的顺铂敏感性。本研究表明GJB2是通过上调TNC表达克服OC顺铂耐药的潜在治疗靶点。表儿茶素可能通过靶向GJB2增强顺铂疗效。

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引用次数: 0

NRAMP family in plants: Contribution to cadmium accumulation 植物NRAMP家族：对镉积累的贡献。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-04 DOI: 10.1016/j.bbamcr.2025.120056

Katarzyna Kozak , Danuta Maria Antosiewicz

The Natural Resistance Associated Macrophage Proteins (NRAMPs) are membrane-targeted transporters with low substrate specificity, that mediate the import (translocation to the cytoplasm) of metals, mainly essential nutrients, e.g. iron (Fe), manganese (Mn), zinc (Zn), cobalt (Co), copper (Cu) or nickel (Ni). Depending on the subcellular localisation, they contribute to either uptake or redistribution. Numerous studies have shown that NRAMP proteins also mediate the transport of non-essential toxic metals, and constitute the major pathway for the uptake of cadmium (Cd) in plants. Given the threat to living organisms from exposure to this toxic metal, which enters the food chain through edible plant parts, this review focuses on how different NRAMP proteins are involved in Cd uptake and accumulation. The issue was discussed concerning three categories of plants: (i) the model plant Arabidopsis thaliana; (ii) crop plants that are mainly used for food; (iii) plant species used for the phytoremediation of Cd-polluted environments, including hyperaccumulators. For the sake of clarity, this paper updates the structure, function and regulation of NRAMP genes and proteins, their phylogenetic relationships, and their substrates, filling a knowledge gap, and discussing these topics in light of new data. Furthermore, this review discusses the potential applications of NRAMP genes in plant biotechnology, such as generating low-Cd food and phytoremediation.

天然耐药相关巨噬细胞蛋白（NRAMPs）是一种低底物特异性的膜靶向转运蛋白，介导金属的进口（转运到细胞质），主要是必需营养素，如铁（Fe）、锰（Mn）、锌（Zn）、钴（Co）、铜（Cu）或镍（Ni）。根据亚细胞定位的不同，它们有助于摄取或重新分配。大量研究表明，NRAMP蛋白还介导非必需有毒金属的转运，并构成植物吸收镉（Cd）的主要途径。鉴于暴露于这种有毒金属对生物体的威胁，这种金属通过可食用的植物部分进入食物链，本综述侧重于不同的NRAMP蛋白如何参与Cd的吸收和积累。讨论了三类植物的问题：(1)模式植物拟南芥；（二）主要用于食用的农作物；（iii）用于cd污染环境的植物修复的植物物种，包括超积累植物。为了清晰起见，本文更新了NRAMP基因和蛋白的结构、功能和调控、它们的系统发育关系以及它们的底物，填补了知识空白，并结合新的数据对这些主题进行了讨论。此外，本文还对NRAMP基因在低镉食品生产和植物修复等植物生物技术方面的潜在应用进行了综述。

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引用次数: 0

TXNIP promotes ferroptosis through NCOA4 mediated ferritinophagy TXNIP通过NCOA4介导的铁蛋白自噬促进铁凋亡。

IF 3.7 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research

Pub Date : 2025-09-04 DOI: 10.1016/j.bbamcr.2025.120054

Pandian Nagakannan , Md Imamul Islam , Shakila Sultana , Soheila Karimi-Abdolrezaee , Eftekhar Eftekharpour

Ferroptosis is a recently discovered lytic form of cell death that is triggered by iron-driven excessive lipid peroxidation and depletion of glutathione and glutathione peroxidase-4 (GPX4). This form of cell death has been linked to a wide range of conditions from cancer to neurodegenerative diseases. Using murine hippocampal HT22 neurons, we aimed to investigate the underlying mechanisms of glutamate-mediated ferroptosis. A robust increase in Thioredoxin-Inhibiting Protein (TXNIP) prompted us to use genetic approaches and examine the role of this protein in ferroptosis in HT22 neurons, mouse embryonic fibroblasts, and Hela cells. Our results indicate that TXNIP is a key player in ferroptotic pathway, as its deletion conferred resistance to classic ferroptosis-inducing agents (erastin, RSL3, and ML210), while TXNIP overexpression increased their susceptibility to ferroptosis. Notably, TXNIP deletion protected cells from mitochondrial dysfunction induced by ferroptotic agents, independent of GSH and GPX4 levels. We further showed that TXNIP mediates ferroptosis through facilitating degradation of the iron-binding protein ferritin via NCOA4-mediated ferritinophagy. This resulted in elevated cytosolic labile iron levels, therefore amplifying lipid peroxidation, and promoting ferroptosis. Our findings suggest that TXNIP acts as a positive regulator of ferroptosis by modulating autophagy and iron availability. Targeting TXNIP might hold promise in developing drugs for diseases involving the ferroptotic pathway.

Ferroptosis是最近发现的一种细胞死亡的溶解形式，由铁驱动的过度脂质过氧化和谷胱甘肽和谷胱甘肽过氧化物酶-4 （GPX4）的消耗引发。这种形式的细胞死亡与从癌症到神经退行性疾病的广泛疾病有关。利用小鼠海马HT22神经元，我们旨在探讨谷氨酸介导的铁下垂的潜在机制。硫氧还蛋白抑制蛋白（TXNIP）的显著增加促使我们使用遗传方法并检测该蛋白在HT22神经元、小鼠胚胎成纤维细胞和Hela细胞中铁凋亡中的作用。我们的研究结果表明，TXNIP是铁凋亡途径的关键参与者，因为它的缺失使其对经典的铁凋亡诱导药物（erastin， RSL3和ML210）产生抗性，而TXNIP的过表达增加了它们对铁凋亡的易感性。值得注意的是，TXNIP缺失可以保护细胞免受不依赖于GSH和GPX4水平的致铁剂诱导的线粒体功能障碍。我们进一步表明，TXNIP通过ncoa4介导的铁蛋白噬噬促进铁结合蛋白铁蛋白的降解，从而介导铁凋亡。这导致细胞质不稳定铁水平升高，因此放大脂质过氧化，并促进铁下垂。我们的研究结果表明，TXNIP通过调节自噬和铁的可用性作为铁凋亡的积极调节剂。以TXNIP为靶点，可能为开发涉及铁致凋亡途径的疾病的药物带来希望。

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