Cellular signalling最新文献_第8页

Targeting CDK12 rescues C/EBPβ-mediated platinum and PARP inhibitor resistance in ovarian cancer 靶向CDK12可缓解C/ ebp β介导的卵巢癌铂和PARP抑制剂耐药

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-16 DOI: 10.1016/j.cellsig.2025.112328

Jiahong Tan , Wei Dong , Daoqi Wang , Aiqing Tu , Zuheng Wang , Xiaodie Wu , Fen Zhang , Yun Zhu , Li Ren , Ying Ai , Yun Feng , Jie Zhang

Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian cancer. Here, we found that ovarian cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian cancer, thereby counteracting platinum and PARP inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian cancer.

尽管采取了多种治疗方法，但对铂和PARP抑制剂的耐药性是改善卵巢癌预后的主要障碍。在这里，我们发现卵巢癌组织与正常组织相比有更高的C/EBPβ表达，高C/EBPβ表达预示着不利的生存结果。升高的C/EBPβ表达增强顺铂耐药和奥拉帕尼耐药。C/EBPβ可影响卵巢癌DDR信号。CDK12作为C/EBPβ调控的ddr相关基因，被C/EBPβ直接靶向并结合。C/EBPβ可促进CDK12表达，并通过CDK12赋予药物耐受性。操纵CDK12可以逆转C/EBPβ的作用。使用CDK12抑制剂THZ531可以缓解C/ ebp β介导的顺铂耐药和奥拉帕尼耐药。我们的研究结果表明，C/EBPβ是卵巢癌的一种有效的DDR调节剂，它直接靶向CDK12并上调其表达。高C/EBPβ表达通过CDK12介导铂耐药和PARP抑制剂耐药。通过抑制CDK12靶向C/EBPβ可以挽救卵巢癌的药物反应性，从而抵消铂和PARP抑制剂的耐药性。因此，C/EBPβ可以作为卵巢癌的候选预后生物标志物。

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引用次数: 0

JOSD2 alleviates hypertensive renal disease through deubiquitinating AKT in renal tubular epithelial cells JOSD2通过在肾小管上皮细胞中去泛素化AKT减轻高血压肾病。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-16 DOI: 10.1016/j.cellsig.2025.112330

Shijie Fan , Ying Zhao , Luyao Li , Qingqing Zhao , Ziming Fang , Diyun Xu , Jingjing Shao , Yunjie Zhao , Guang Liang , Xuelin He , Hong Zhu , Yi Wang

Hypertensive renal disease (HRD) is a significant driver of end-stage renal disease. Discovering novel therapeutic targets for HRD is essential for its prevention and treatment. Deubiquitinating enzymes (DUBs) have shown increasing significance in renal diseases. Here, we investigated the role and mechanism of the DUB, Josephin domain-containing protein 2 (JOSD2), in HRD. HRD was induced in wild-type or Josd2 knockout mice via a 4-week chronic infusion of angiotensin II (Ang II). We found that deficiency of JOSD2 aggravated renal injury, epithelial-mesenchymal transition (EMT), and fibrosis in HRD mice. Single-cell RNA-seq analysis indicated that JOSD2 is mainly expressed in tubular epithelial cells (TECs) of proximal tubules. Notably, the specific overexpression of JOSD2 in renal TECs alleviated the detrimental effects in Ang II-induced HRD mice. Mechanistically, through mass spectrometry combined with co-immunoprecipitation analysis, we considered protein kinase B (AKT) as a potential substrate of JOSD2. JOSD2 deubiquitinated the K63-linked ubiquitin chain of AKT via its active site H125 and then enhanced p62-mediated autophagic degradation of AKT. This process reduced the AKT level in TECs, thereby ultimately reducing renal EMT and fibrosis. Our study elucidates the role of the JOSD2-AKT axis in HRD and suggests that JOSD2 may serve as a promising therapeutic target for HRD.

高血压肾病（HRD）是终末期肾脏疾病的重要驱动因素。发现新的HRD治疗靶点对其预防和治疗至关重要。去泛素化酶（DUBs）在肾脏疾病中的作用越来越重要。在这里，我们研究了Josephin结构域蛋白2 （JOSD2）在HRD中的作用和机制。在野生型或Josd2基因敲除小鼠中，通过4周的血管紧张素II （Ang II）慢性输注诱导HRD。我们发现，缺乏JOSD2会加重HRD小鼠的肾损伤、上皮-间质转化（EMT）和纤维化。单细胞RNA-seq分析表明，JOSD2主要表达于近端小管上皮细胞（TECs）中。值得注意的是，JOSD2在肾tec中的特异性过表达减轻了Ang ii诱导的HRD小鼠的有害影响。从机制上讲，通过质谱结合共免疫沉淀分析，我们认为蛋白激酶B （AKT）是JOSD2的潜在底物。JOSD2通过其活性位点H125使AKT的k63连接的泛素链去泛素化，进而增强p62介导的AKT自噬降解。这一过程降低了TECs中的AKT水平，从而最终减少肾脏EMT和纤维化。我们的研究阐明了JOSD2- akt轴在HRD中的作用，并提示JOSD2可能作为HRD的一个有希望的治疗靶点。

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引用次数: 0

Blockade of CD47 signaling improves ferroptosis of lung cancer cells via activating Nrf2/FPN signaling 阻断CD47信号通路可通过激活Nrf2/FPN信号通路改善肺癌细胞铁下垂。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-16 DOI: 10.1016/j.cellsig.2025.112331

Lu Hu , Chun Li , Miaomiao Chen , Qiwen Zhou , Zhilong Jiang

CD47 plays an important role in immune evasion through suppressing macrophage phagocytosis. CD47 blockade has been widely explored in immunotherapy of cancers through enhancing macrophage phagocytosis. However, the role of CD47 in lung cancer cell apoptosis and ferroptosis is not well defined. In this study, we found that CD47 was highly expressed and ferroportin (FPN) was low expressed in lung cancer cells. Over-expression of CD47 increased the expression of Nrf2 (Nuclear factor erythroid 2-related factor 2); but suppressed the expression of FPN. Knock-down and blockade of CD47 expression and activity suppressed the expression of Nrf2 and enhanced the expression of FPN, subsequently improved lung cancer cell ferroptosis, accompanied with increased expression of pro-apoptotic protein Bax, production of reactive oxygen species (ROS) and hemosiderin deposition. Suppression of Nrf2 activity by Brusatol increased FPN expression at a concentration-dependent manner; whereas over-expression of FPN increased lung cancer cell ferroptosis. More studies in mouse model showed that knockdown of CD47 effectively attenuated lung cancer cell growth after subcutaneous inoculation of shCD47-pretreated LLC cells, associated with increased infiltration of neutrophils, CD8+ T cells and Malondialdehyde (MDA) products. Meanwhile, the expressions of TNF-α, IL-6 and IL-1β were elevated in the treated tumor tissues. IL-6 and TNF-α suppressed the expression of CD47, but increased the expression of FPN, accompanied with elevated expression of Bax, Cleaved caspase-3, NCOA4 (Nuclear receptor coactivator 4). Therefore, blockade of CD47 expression attenuated lung cancer growth through suppressing Nrf2 and subsequently increasing the expression of FPN. CD47 exerts immune evasion via Nrf2/FPN axis.

CD47通过抑制巨噬细胞吞噬在免疫逃避中发挥重要作用。CD47阻断剂通过增强巨噬细胞吞噬作用在肿瘤免疫治疗中被广泛探索。然而，CD47在肺癌细胞凋亡和铁下垂中的作用尚未明确。在本研究中，我们发现CD47在肺癌细胞中高表达，而铁转运蛋白（FPN）在肺癌细胞中低表达。过表达CD47可增加Nrf2（核因子-红细胞2相关因子2）的表达；抑制FPN的表达。敲除和阻断CD47的表达和活性抑制Nrf2的表达，增强FPN的表达，从而改善肺癌细胞的铁凋亡，并伴有促凋亡蛋白Bax的表达增加，活性氧（ROS）的产生和含铁血黄素的沉积。Brusatol对Nrf2活性的抑制使FPN表达呈浓度依赖性增加；而过表达FPN则增加肺癌细胞铁下垂。小鼠模型的更多研究表明，皮下接种shcd47预处理LLC细胞后，敲低CD47可有效减弱肺癌细胞的生长，并与中性粒细胞、CD8+ T细胞和丙二醛（MDA）产物的浸润增加有关。同时，肿瘤组织中TNF-α、IL-6、IL-1β的表达升高。IL-6和TNF-α抑制CD47的表达，增加FPN的表达，同时Bax、Cleaved caspase-3、NCOA4（核受体共激活因子4）的表达升高。因此，阻断CD47表达可通过抑制Nrf2从而增加FPN的表达来减弱肺癌的生长。CD47通过Nrf2/FPN轴进行免疫逃避。

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引用次数: 0

Interferon regulatory factor 1 promotes pyroptosis and inflammation in mouse sepsis-induced cardiomyopathy 干扰素调节因子1促进小鼠败血症诱导的心肌病的焦亡和炎症。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-16 DOI: 10.1016/j.cellsig.2025.112332

Meng-Qin Pei , Ya-Fen Zeng , Yu-Shen Yang , Yu-Ming Fang , Shu Lin , Jin-Wei Liang , He-Fan He

Although pyroptosis is involved in sepsis and sepsis-induced cardiomyopathy (SIC), the underlying mechanism remains unclear. This study aimed to investigate the role and mechanims of myocardial pyroptosis in the progression of SIC. We first identified differentially expressed genes and hub pyroptosis-related genes (PRGs) in SIC using bioinformatics analyses and then constructed in vitro and in vivo SIC models to reveal the specific mechanisms of hub PRGs in SIC development. In this study, we confirmed eight hub PRGs (caspase-1, IRF1, IL-6, GSDMD, caspase-6, IL-1β, caspase-8, and ZBP1) as potential candidate biomarkers for SIC and their expression change in cardiac tissue and myocardial cells in sepsis was fully validated through a serials of in vivo and in vitro experiments. Additionally, KEGG analysis displayed that these hub PRGs were enriched for NOD-like receptor (NLR) signaling pathways and IRF1 is an upstream regulator of the NLRP3 inflammasome. SIC mice treated with IRF1 inhibitor, N-acetyl- l-cysteine (NAC), showed notable amelioration of cardiac histological injury, reduced levels of myocardial injury markers, and decreased expression of NLRP3, pyroptosis-related markers, and pro-inflammatory factors. The IRF1-knockdown H9C2 cells also exhibited markedly reduced expression of pro-inflammatory factors and pyroptosis-related markers. Overall, these findings suggest that IRF1 deficiency attenuates sepsis-induced myocardial injury by inhibiting pyroptosis and inflammation. Therefore, targeting IRF1 in cardiomyocytes may be a promising therapeutic strategy for preventing SIC.

虽然焦亡与脓毒症和脓毒症引起的心肌病（SIC）有关，但其潜在机制尚不清楚。本研究旨在探讨心肌焦亡在SIC进展中的作用和机制。我们首先利用生物信息学分析方法鉴定了SIC中差异表达基因和hub pyrotosis相关基因（PRGs），然后构建了体外和体内SIC模型，以揭示hub PRGs在SIC发育中的具体机制。在本研究中，我们证实了8个中心PRGs （caspase-1、IRF1、IL-6、GSDMD、caspase-6、IL-1β、caspase-8和ZBP1）是SIC的潜在候选生物标志物，并且通过一系列体内和体外实验充分验证了它们在脓毒症中心脏组织和心肌细胞中的表达变化。此外，KEGG分析显示，这些中枢PRGs富集于nod样受体（NLR）信号通路，IRF1是NLRP3炎性体的上游调节因子。用IRF1抑制剂n -乙酰- l-半胱氨酸（NAC）处理的SIC小鼠，心肌组织损伤显著改善，心肌损伤标志物水平降低，NLRP3、焦热相关标志物和促炎因子的表达降低。irf1敲低的H9C2细胞也表现出促炎因子和焦热相关标志物的表达显著降低。总之，这些发现表明IRF1缺乏通过抑制焦亡和炎症减轻败血症引起的心肌损伤。因此，靶向心肌细胞中的IRF1可能是预防SIC的一种有前景的治疗策略。

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引用次数: 0

RBP-J-mediated suppression of LINC00324 promotes ferroptosis via SLC3A2 in silica-induced pulmonary fibrosis rbp - j介导的LINC00324抑制通过SLC3A2在二氧化硅诱导的肺纤维化中促进铁凋亡。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-15 DOI: 10.1016/j.cellsig.2025.112329

Wenlong Wu , Ling Huang , Wanqing Fang , Wanrong Wang , Sijing Zhou , Ran Wang

Background

Silica-induced pulmonary fibrosis involves epithelial-mesenchymal transition(EMT) and ferroptosis, but the regulatory roles of long non-coding RNAs in these processes remain unclear. This study investigates the role of LINC00324 in ferroptosis and EMT which contribute to silica-induced pulmonary fibrosis.

Methods

A549 and BEAS-2B were exposed to SiO₂ (100 μg/mL, 24 h). Molecular analyses included chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, RNA immunoprecipitation, and functional rescue experiments. In vivo validation C57BL/6 mice were treated with intratracheal silica instillation (50 mg/kg) and lentiviral-mediated SLC3A2 overexpression (5 × 10⁷ TU), followed by histopathological/biochemical analyses at day 28.

Results

Silica exposure transcriptionally suppressed LINC00324 via impaired RBP-J binding to its promoter region. LINC00324 overexpression mitigated silica-induced ferroptosis and EMT, while its knockdown aggravated ferroptosis and EMT. Further studies showed that LINC00324 played a regulatory role in ferroptosis and EMT through SLC3A2. RBP-J, as a transcription factor upstream of LINC00324, regulates ferroptosis and EMT in silica-induced pulmonary fibrosis through SLC3A2. In vivo, SLC3A2 overexpression alleviated silica-induced pulmonary fibrosis.

Conclusion

Collectively, the RBP-J/LINC00324/SLC3A2 pathway regulates ferroptosis -EMT coupling in silicosis. RBP-J regulates ferroptosis and EMT by binding to the promoter region of LINC00324 and regulating the downstream SLC3A2. Therapeutic targeting of this pathway may combat silica-induced pulmonary fibrosis.

背景：二氧化硅诱导的肺纤维化涉及上皮-间质转化（EMT）和铁凋亡，但长链非编码rna在这些过程中的调节作用尚不清楚。本研究探讨了LINC00324在二氧化硅诱导肺纤维化的铁下垂和EMT中的作用。方法：A549和BEAS-2B暴露于SiO（100 μg/mL, 24 h）中。分子分析包括染色质免疫沉淀（ChIP）、双荧光素酶报告基因检测、RNA免疫沉淀和功能拯救实验。C57BL/6小鼠经气管内注射二氧化硅（50 mg/kg）和慢病毒介导的SLC3A2过表达（5 × 107 TU），于第28天进行组织病理/生化分析。结果：二氧化硅暴露通过破坏RBP-J与其启动子区域的结合来抑制LINC00324的转录。LINC00324过表达可减轻二氧化硅诱导的铁下垂和EMT，而其敲低可加重铁下垂和EMT。进一步研究表明，LINC00324通过SLC3A2在铁下垂和EMT中发挥调控作用。RBP-J作为LINC00324上游的转录因子，通过SLC3A2调控二氧化硅诱导肺纤维化中的铁凋亡和EMT。在体内，SLC3A2过表达可减轻二氧化硅诱导的肺纤维化。结论：RBP-J/LINC00324/SLC3A2通路共同调控矽肺中铁ptosis -EMT偶联。RBP-J通过结合LINC00324的启动子区，调控下游SLC3A2调控铁下垂和EMT。靶向治疗这一途径可以对抗二氧化硅诱导的肺纤维化。

{"title":"RBP-J-mediated suppression of LINC00324 promotes ferroptosis via SLC3A2 in silica-induced pulmonary fibrosis","authors":"Wenlong Wu , Ling Huang , Wanqing Fang , Wanrong Wang , Sijing Zhou , Ran Wang","doi":"10.1016/j.cellsig.2025.112329","DOIUrl":"10.1016/j.cellsig.2025.112329","url":null,"abstract":"<div><h3>Background</h3><div>Silica-induced pulmonary fibrosis involves epithelial-mesenchymal transition(EMT) and ferroptosis, but the regulatory roles of long non-coding RNAs in these processes remain unclear. This study investigates the role of LINC00324 in ferroptosis and EMT which contribute to silica-induced pulmonary fibrosis.</div></div><div><h3>Methods</h3><div>A549 and BEAS-2B were exposed to SiO₂ (100 μg/mL, 24 h). Molecular analyses included chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, RNA immunoprecipitation, and functional rescue experiments. In vivo validation C57BL/6 mice were treated with intratracheal silica instillation (50 mg/kg) and lentiviral-mediated SLC3A2 overexpression (5 × 10<sup>7</sup> TU), followed by histopathological/biochemical analyses at day 28.</div></div><div><h3>Results</h3><div>Silica exposure transcriptionally suppressed LINC00324 via impaired RBP-J binding to its promoter region. LINC00324 overexpression mitigated silica-induced ferroptosis and EMT, while its knockdown aggravated ferroptosis and EMT. Further studies showed that LINC00324 played a regulatory role in ferroptosis and EMT through SLC3A2. RBP-J, as a transcription factor upstream of LINC00324, regulates ferroptosis and EMT in silica-induced pulmonary fibrosis through SLC3A2. In vivo, SLC3A2 overexpression alleviated silica-induced pulmonary fibrosis.</div></div><div><h3>Conclusion</h3><div>Collectively, the RBP-J/LINC00324/SLC3A2 pathway regulates ferroptosis -EMT coupling in silicosis. RBP-J regulates ferroptosis and EMT by binding to the promoter region of LINC00324 and regulating the downstream SLC3A2. Therapeutic targeting of this pathway may combat silica-induced pulmonary fibrosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112329"},"PeriodicalIF":3.7,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The trilateral crosstalk of TGF β1-ROS-Nrf2 axis in fibrosis: Decoding mechanistic networks for precision therapeutics TGF β1-ROS-Nrf2轴在纤维化中的三边串扰：解码精准治疗的机制网络。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-15 DOI: 10.1016/j.cellsig.2025.112327

Yaya Gao , Qingli Yu , Hanwen Zhu , Yunhan Zhang , Hui Yang

Fibrosis, a hallmark pathological process in numerous chronic diseases, is characterized by the excessive accumulation of extracellular matrix (ECM) components, primarily driven by activated myofibroblasts. This dysregulated tissue remodeling arises from a complex imbalance between pro-fibrotic and anti-fibrotic signaling pathways. The transforming growth factor-beta 1 (TGF-β1) signaling pathway, particularly its canonical Smad-dependent arm, is widely recognized as a master regulator orchestrating fibrotic responses. Compelling evidence underscores the critical contributions of reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) to fibrogenesis, acting both independently and through intricate crosstalk with TGF-β1 signaling. Nrf2 serves as the master transcriptional regulator of the antioxidant response, binding to antioxidant response elements (AREs) to induce the expression of a battery of cytoprotective and detoxifying enzymes, thereby mitigating oxidative stress. This review comprehensively dissects the individual and interconnected roles of TGF-β1, ROS, and Nrf2 in driving the molecular pathogenesis of fibrosis and explores the emerging therapeutic strategies targeting this axis.

纤维化是许多慢性疾病的标志性病理过程，其特征是细胞外基质（ECM）成分的过度积累，主要由活化的肌成纤维细胞驱动。这种失调的组织重塑源于促纤维化和抗纤维化信号通路之间复杂的不平衡。转化生长因子-β1 （TGF-β1）信号通路，特别是其典型的smad依赖性分支，被广泛认为是协调纤维化反应的主要调节因子。令人信服的证据强调了活性氧（ROS）和核因子红细胞2相关因子2 （Nrf2）对纤维形成的重要贡献，它们既独立作用，也通过与TGF-β1信号的复杂串扰作用。Nrf2作为抗氧化反应的主要转录调节因子，与抗氧化反应元件（AREs）结合，诱导一系列细胞保护和解毒酶的表达，从而减轻氧化应激。本文全面分析了TGF-β1、ROS和Nrf2在推动纤维化分子发病机制中的个体和相互作用，并探讨了针对该轴的新兴治疗策略。

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引用次数: 0

ADAMTSL2 facilitates ACLY-mediated lipid metabolism in colorectal cancer by activating Notch signaling pathway ADAMTSL2通过激活Notch信号通路促进acly介导的结直肠癌脂质代谢。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-15 DOI: 10.1016/j.cellsig.2025.112319

Xuan He , Ming Li , Jianpeng Liu , Xiangwei Zeng

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, characterized by complex metabolic alterations and aberrant signaling pathways. Although ADAMTSL2 has been associated with tumor progression, its functional role in CRC remains unclear. In this study, we identified elevated ADAMTSL2 expression in CRC tissues from the TCGA-COADREAD cohort, where it correlated with poor patient survival. Functional experiments using HCT116 and SW620 cell lines, along with patient-derived organoids, demonstrated that ADAMTSL2 knockdown suppressed proliferation and migration. These findings were further supported by reduced tumor growth in ADAMTSL2-silenced xenograft models. Mechanistically, we uncovered a novel ADAMTSL2-Notch-ACLY axis, through which ADAMTSL2 activates Notch signaling to transcriptionally upregulate ACLY, driving lipid metabolic reprogramming. Our results establish ADAMTSL2 as a key prognostic biomarker and a potential therapeutic target in CRC, highlighting the clinical relevance of its regulation of Notch-ACLY-mediated metabolic plasticity.

结直肠癌（CRC）是全球癌症相关死亡的主要原因，其特征是复杂的代谢改变和异常的信号通路。虽然ADAMTSL2与肿瘤进展有关，但其在结直肠癌中的功能作用尚不清楚。在这项研究中，我们从TCGA-COADREAD队列中发现了CRC组织中ADAMTSL2表达升高，这与患者生存率低相关。使用HCT116和SW620细胞系以及患者来源的类器官进行的功能实验表明，ADAMTSL2敲低可抑制增殖和迁移。在adamtsl2沉默的异种移植物模型中，肿瘤生长减少进一步支持了这些发现。在机制上，我们发现了一个新的ADAMTSL2-Notch-ACLY轴，通过该轴，ADAMTSL2激活Notch信号，转录上调ACLY，从而驱动脂质代谢重编程。我们的研究结果确立了ADAMTSL2作为结直肠癌关键的预后生物标志物和潜在的治疗靶点，强调了其调节notch - acly介导的代谢可塑性的临床相关性。

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引用次数: 0

Redox guardian or oncogenic driver? The dual roles of PRDX1 in tumorigenesis 氧化还原守护者还是致癌驱动因素？PRDX1在肿瘤发生中的双重作用。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-15 DOI: 10.1016/j.cellsig.2025.112310

Li Wang , Yi-di Deng , Jian-wei Yang , Chang-yan Li , Lan-chun Shao , Li Yang , Jin Chai , Shan-hui Liu , Si-yu Chen

Peroxiredoxin 1 (PRDX1) is a thiol-dependent peroxidase with paradoxical roles in cancer. In response to oxidative stress and hyperoxidation of its peroxidatic cysteine, PRDX1 undergoes reversible oligomerization, switching from a peroxidase to a molecular chaperone, thereby dictating context-dependent tumor effects. In early malignancy, PRDX1 suppresses transformation by limiting oxidative DNA damage and inhibiting oncogenic signaling (c-Myc, PTEN/AKT). However, PRDX1 overexpression in advanced cancers promotes survival, proliferation, and chemoresistance via MAPK modulation, DNA repair enhancement, and tumor microenvironment remodeling via TLR4-mediated immune modulation. Elevated PRDX1 correlates with poor prognosis in lung, breast, liver, bladder, and colorectal cancers. Pharmacological targeting with covalent inhibitors (celastrol derivatives, adenanthin, natamycin) induces oxidative stress and apoptosis in preclinical models, yet isoform selectivity and patient stratification remain unresolved. This review synthesizes PRDX1's dual tumor-suppressive and oncogenic functions, highlighting mechanisms underlying its redox-switching behavior and exploring its potential as a diagnostic biomarker and therapeutic target. Understanding PRDX1's structural dynamics and protein interactions will enable rational design of context-appropriate interventions in precision oncology.

过氧化物还蛋白1 （PRDX1）是一种硫醇依赖性过氧化物酶，在癌症中具有矛盾的作用。在氧化应激和其过氧化物半胱氨酸的高氧化反应中，PRDX1经历了可逆的寡聚化，从过氧化物酶转变为分子伴侣，从而决定了上下文依赖的肿瘤效应。在早期恶性肿瘤中，PRDX1通过限制DNA氧化损伤和抑制致癌信号传导（c-Myc, PTEN/AKT）来抑制转化。然而，PRDX1在晚期癌症中的过表达通过MAPK调节、DNA修复增强和tlr4介导的免疫调节介导的肿瘤微环境重塑来促进生存、增殖和化疗耐药。PRDX1升高与肺癌、乳腺癌、肝癌、膀胱癌和结直肠癌预后不良相关。在临床前模型中，共价抑制剂（celastrol衍生物、腺嘌呤、纳他霉素）的药理靶向可诱导氧化应激和细胞凋亡，但同种异构体的选择性和患者分层仍未解决。本文综合了PRDX1的双重肿瘤抑制和致癌功能，强调了其氧化还原开关行为的机制，并探索了其作为诊断生物标志物和治疗靶点的潜力。了解PRDX1的结构动力学和蛋白质相互作用将有助于在精确肿瘤学中合理设计适合具体情况的干预措施。

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引用次数: 0

hPMSC-derived Exosomal miR-26-5p modulates macrophage polarization for liver repair in DILI via PTEN/mTOR signaling hpmsc衍生的外泌体miR-26-5p通过PTEN/mTOR信号调节巨噬细胞极化，促进DILI中的肝脏修复。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-13 DOI: 10.1016/j.cellsig.2025.112272

Zhi Zhang , Yu Fu , Shuyi Wei , Liwei Liang , Ting Li , Lei Feng , Lei Cai , Shunjun Fu , Yang Li , Shao Li , Mingxin Pan , Guolin He

Background: The paracrine mechanisms of Mesenchymal Stem Cells (MSCs) involve the release of bioactive components, including exosomes. Although the crucial role of macrophage polarization in acute liver injury has been established by previous studies, further elucidation is needed regarding the influence of exosome-mediated liver repair on macrophage polarization. Methods: Mice were intravenously administered with exosomes derived from human placental mesenchymal stem cells (hPMSC-Exo) 2 h prior to LPS/GalN exposure. The effects of hPMSC-Exo were assessed through analyses of serum biochemistry, TUNEL assay, and H&E staining. To elucidate the mechanisms involved in acute liver injury therapy, gene expression levels were determined through qPCR and Western blot analysis, respectively. Exosomes transfected with miR-26-5p were utilized to investigate the involvement of mTOR signaling in hPMSC-Exo-based therapy. In a mouse model of D-galN/LPS-induced DILI (drug-induced liver injury), hPMSC-Exo mitigated liver inflammation and facilitated liver repair. Subsequent investigations demonstrated that hPMSC-Exo induced the shift of M1 macrophages towards an M2 phenotype, both in vivo and in vitro. miRNA sequencing and Bioinformatics analysis identified miR-26-5p as a potential mediator that drives macrophage polarization, with PTEN identified as its downstream target. Reducing the levels of miR-26-5p in hPMSC-Exo resulted in attenuated modulation of macrophage polarization. Knockdown of PTEN similarly exhibited hepatoprotective efficacy and reduced inflammation levels in a mouse model of DILI. Conclusion: Based on our findings, it is suggested that the PTEN/mTOR/TGF-β1 signaling pathway is involved in regulating macrophage activation through hPMSC exosomal miR-26-5p, thereby highlighting its therapeutic potential in liver injury treatment.

背景：间充质干细胞（MSCs）的旁分泌机制涉及生物活性成分的释放，包括外泌体。虽然前期研究已证实巨噬细胞极化在急性肝损伤中的重要作用，但外泌体介导的肝修复对巨噬细胞极化的影响尚需进一步阐明。方法：小鼠在LPS/GalN暴露前静脉注射人胎盘间充质干细胞（hPMSC-Exo） 2 衍生的外泌体。通过血清生化分析、TUNEL试验和H&E染色评估hPMSC-Exo的作用。为了阐明参与急性肝损伤治疗的机制，分别通过qPCR和Western blot分析检测基因表达水平。利用转染miR-26-5p的外泌体来研究mTOR信号在hpmsc - exo治疗中的作用。在D-galN/ lps诱导的DILI（药物性肝损伤）小鼠模型中，hPMSC-Exo减轻了肝脏炎症并促进了肝脏修复。随后的研究表明，在体内和体外，hPMSC-Exo诱导M1巨噬细胞向M2表型转移。miRNA测序和生物信息学分析发现miR-26-5p是驱动巨噬细胞极化的潜在介质，PTEN被确定为其下游靶点。降低hPMSC-Exo中miR-26-5p的水平导致巨噬细胞极化的调节减弱。在DILI小鼠模型中，PTEN的敲低同样表现出肝脏保护作用和降低炎症水平。结论：基于我们的研究结果，提示PTEN/mTOR/TGF-β1信号通路通过hPMSC外泌体miR-26-5p参与调控巨噬细胞活化，从而凸显其在肝损伤治疗中的治疗潜力。

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引用次数: 0

Unraveling the secrets of UBE2S in endometrial cancer: Potential targets for diagnosis, prognostic assessment, and ferroptosis therapy 揭示子宫内膜癌中UBE2S的秘密：诊断、预后评估和铁下垂治疗的潜在靶点。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-12-13 DOI: 10.1016/j.cellsig.2025.112325

Haodi Yue , Mengjun Zhang , Jingyi Lu , Zidi Zhang , Jialin Wang , Yan Guo

Background

UBE2S exhibits elevated expression in various cancers. Its overexpression is positively correlated with poor prognosis in endometrial cancer (UCEC) patients. However, the role and underlying mechanisms of UBE2S in UCEC progression remain to be fully elucidated.

Methods

Utilizing TCGA data, we initially identified UBE2S as a prognostically significant gene. Subsequently, We evaluated UBE2S expression levels in UCEC tumor tissues and cell lines using immunohistochemistry (IHC), qRT-PCR and Western blotting. Following shRNA-mediated knockdown of UBE2S, we systematically assessed its effects on cell proliferation and migration through CCK-8, EdU staining, colony formation, wound healing, and Transwell migration assays. These findings were further validated through in vivo experiments. RNA sequencing (RNA-seq) and TCGA data analysis revealed the cellular biological functions mediated by UBE2S. Flow cytometry and FerroOrange staining were used to examine the effects of UBE2S knockdown on the cell cycle, apoptosis, and ferroptosis. Western blotting was utilized to confirm changes in the expression of proteins associated with these pathways.

Results

A prediction model based on five core UBE2-genes demonstrated significant prognostic value. Notably, UBE2S exhibited significantly elevated expression in UCEC tissues, which was strongly correlated with adverse prognosis and tumor immunosuppressive microenvironment. Additionally, UBE2S knockdown resulted in the suppression of malignant phenotypes in UCEC cells, characterized by reduced cell proliferation and migration both in vitro and in vivo. Furthermore, downregulation of UBE2S induced cell cycle arrest, enhanced apoptosis, and increased ferroptosis.

Conclusions

As a potential oncogene and therapeutic target in UCEC, UBE2S may play a critical role in UCEC cell malignancies.

背景：UBE2S在多种癌症中表达升高。其过表达与子宫内膜癌（UCEC）患者预后不良呈正相关。然而，UBE2S在UCEC进展中的作用和潜在机制仍未完全阐明。方法：利用TCGA数据，我们初步确定UBE2S是一个具有预后意义的基因。随后，我们利用免疫组织化学（IHC）、qRT-PCR和Western blotting检测UBE2S在UCEC肿瘤组织和细胞系中的表达水平。在shrna介导的UBE2S敲低后，我们通过CCK-8、EdU染色、菌落形成、伤口愈合和Transwell迁移试验系统地评估了其对细胞增殖和迁移的影响。这些发现通过体内实验得到了进一步的验证。RNA测序（RNA-seq）和TCGA数据分析揭示了UBE2S介导的细胞生物学功能。流式细胞术和铁橙染色检测UBE2S敲除对细胞周期、凋亡和铁凋亡的影响。Western blotting用于证实与这些通路相关的蛋白表达的变化。结果：基于5个核心ube2基因的预测模型具有显著的预后价值。值得注意的是，UBE2S在UCEC组织中表达显著升高，与不良预后和肿瘤免疫抑制微环境密切相关。此外，UBE2S敲低导致UCEC细胞的恶性表型受到抑制，其特征是细胞在体外和体内的增殖和迁移减少。此外，下调UBE2S诱导细胞周期阻滞、细胞凋亡增强和铁下垂增加。结论：UBE2S作为UCEC潜在的致癌基因和治疗靶点，可能在UCEC细胞恶性肿瘤中发挥关键作用。

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