Cellular signalling最新文献_第4页

Annexin A5 ameliorates immune-mediated liver injury by regulating ferritinophagy–ferroptosis in M2 macrophages via the NRF2/ERK pathway 膜联蛋白A5通过NRF2/ERK通路调节M2巨噬细胞的铁蛋白吞噬-铁凋亡，改善免疫介导的肝损伤。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-12 DOI: 10.1016/j.cellsig.2026.112366

Junfeng Li , Zibing Qian , Zheyu Li , Xiaorong Mao , Aipin Tian , Xuebin Peng , Zhongxia Yang , Kai Yang

Background & aim

M2 macrophages are key drivers of immune-mediated liver injury. The aim of this study was to investigate the mechanisms by which Annexin A5 regulates ferroptosis in M2 macrophages and its protective effect against immune liver injury.

Methods

The colocalization of ferroptosis in M2 macrophages from autoimmune hepatitis (AIH) patients and mice with ConA-induced immune liver injury was analyzed via laser confocal microscopy. The effects of ferritinophagy and autophagosomal–lysosomal fusion on the regulation of ferroptosis in M2 macrophages by Annexin A5 were investigated through mCherryGFP–LC3B adenovirus transfection. Ferroptosis of M2 macrophages was studied by using si-RNA and chemical inhibitors and agonist of nuclear factor erythroid 2-related factor 2 (NRF2) and extracellular signal-regulated kinase (ERK). Bone marrow-derived macrophages were polarized into M2 macrophages for use in cell transfer experiments. A coculture model of M2 macrophages and hepatocytes was established to study the effect of M2 macrophages on liver regeneration.

Results

M2 macrophages are highly sensitive to ferroptosis in immune-mediated liver injury, and Annexin A5 can effectively inhibit ferroptosis in M2 macrophages, thereby exerting a protective effect on immune-mediated liver injury. Annexin A5 alleviates ferritinophagy by inhibiting the degradation of NRF2 and the phosphorylation of ERK1/2, as well as by inhibiting autophagosome–lysosome fusion. This enhances the resistance of M2 macrophages to ferroptosis and improves outcomes in immune-related liver injury. Additionally, the inhibition of ferroptosis in M2 macrophages promotes hepatocyte regeneration.

Conclusion

Our findings comprehensively reveal that the modulation of the NRF2-ERK1/2 signaling pathway by Annexin A5 is essential for mitigating ferroptosis in M2 macrophages during immune-mediated liver injury. Therefore, targeting Annexin A5 may offer novel therapeutic approaches for the treatment of immune-mediated liver injury.

背景与目的：M2巨噬细胞是免疫介导的肝损伤的关键驱动因子。本研究旨在探讨膜联蛋白A5调控M2巨噬细胞铁凋亡的机制及其对免疫性肝损伤的保护作用。方法：采用激光共聚焦显微镜观察自身免疫性肝炎（AIH）患者和cona诱导的免疫性肝损伤小鼠M2巨噬细胞中铁凋亡的共定位。通过转染mCherryGFP-LC3B腺病毒，研究铁蛋白自噬和自噬体-溶酶体融合对Annexin A5调控M2巨噬细胞铁凋亡的影响。采用si-RNA、核因子-红细胞2相关因子- 2 （NRF2）和细胞外信号调节激酶（ERK）的化学抑制剂和激动剂研究M2巨噬细胞的铁凋亡。骨髓源性巨噬细胞被极化为M2巨噬细胞用于细胞转移实验。建立M2巨噬细胞与肝细胞共培养模型，研究M2巨噬细胞对肝脏再生的影响。结果：免疫介导的肝损伤中，M2巨噬细胞对铁凋亡高度敏感，Annexin A5能有效抑制M2巨噬细胞的铁凋亡，从而对免疫介导的肝损伤起到保护作用。膜联蛋白A5通过抑制NRF2的降解和ERK1/2的磷酸化，以及抑制自噬体与溶酶体的融合来减轻铁蛋白自噬。这增强了M2巨噬细胞对铁凋亡的抵抗力，改善了免疫相关肝损伤的预后。此外，抑制M2巨噬细胞的铁下垂可促进肝细胞再生。结论：我们的研究结果全面揭示了膜联蛋白A5对NRF2-ERK1/2信号通路的调节对于减轻免疫介导的肝损伤中M2巨噬细胞的铁凋亡至关重要。因此，靶向膜联蛋白A5可能为治疗免疫介导性肝损伤提供新的治疗途径。

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引用次数: 0

The YAP1 and EPHA3 receptor tyrosine kinase axis regulates cellular plasticity and treatment response YAP1与EphA3受体酪氨酸激酶协同作用调控前列腺癌细胞可塑性和治疗反应。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-12 DOI: 10.1016/j.cellsig.2026.112368

Marwah M. Al-Mathkour , Abdulrahman M. Dwead , Kezhan Khazaw , Bekir Cinar

The transcriptional coregulator YAP1 and the receptor tyrosine kinase EPHA3 regulate key cellular processes, including cell interactions, motility, survival, tissue development, carcinogenesis, and metastasis. Although their individual roles have been extensively studied, their cooperative functions remain poorly understood. Here, we investigated the relationship between EPHA3 and YAP1 in human prostate tumor tissues and cell models. Integrated transcriptomic and immunological analyses reveal a strong positive correlation between YAP1 and EPHA3 expression, which is significantly associated with tumor progression. EPHA3 knockout reduces cell proliferation and increases sensitivity to the androgen receptor inhibitor enzalutamide and the YAP1-TEAD inhibitor CA3 in vitro. EPHA3 depletion also reduces GTP-bound active RHOA and phosphorylated ERK levels and differentially affects epithelial-mesenchymal transition and cancer stem cell programs. In addition, EPHA3 silencing attenuates cell migration and invasion, an effect dependent on YAP1 activation. Bioinformatics analysis further indicates that high YAP1 and EPHA3 correlate with developmental and EMT-related gene signatures. These results demonstrate that the YAP1-EPHA3 axis is a key mediator of cell survival, plasticity, and tumor progression, and may serve as a promising cancer drug target.

转录共调节剂YAP1和受体酪氨酸激酶EPHA3调节关键的细胞过程，包括细胞相互作用、运动、存活、组织发育、致癌和转移。虽然它们的个体作用已被广泛研究，但它们的合作功能仍然知之甚少。在此，我们研究了EPHA3和YAP1在人前列腺肿瘤组织和细胞模型中的关系。综合转录组学和免疫学分析显示，YAP1和EPHA3的表达呈正相关，与肿瘤进展显著相关。在体外实验中，敲除EPHA3可降低细胞增殖，增加对雄激素受体抑制剂enzalutamide和YAP1-TEAD抑制剂CA3的敏感性。EPHA3缺失也会降低gtp结合的活性RHOA和磷酸化的ERK水平，并对上皮-间质转化和癌症干细胞程序产生不同的影响。此外，EPHA3沉默会减弱细胞迁移和侵袭，这是一种依赖于YAP1激活的效应。生物信息学分析进一步表明，高水平的YAP1和EPHA3与发育和emt相关的基因特征相关。这些结果表明，YAP1-EPHA3轴是细胞存活、可塑性和肿瘤进展的关键介质，可能是一个有希望的癌症药物靶点。

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引用次数: 0

Anti-fibrotic activity of nobiletin and nintedanib: In vitro and in vivo evidence in pulmonary fibrosis models 诺匹莱素和尼达尼布的抗纤维化活性：肺纤维化模型的体外和体内证据。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-12 DOI: 10.1016/j.cellsig.2026.112364

Xue Yang , Yuanru Wang , Luyao Li , Qiqi Lei , Liuyan Xiang , Xiaoqian Zhang , Jie Liu , Yajun Cao , Huifang Li , Xuejun Li

Background

Pulmonary fibrosis, a well-known chronic and progressive lung disease, primarily impacts the interstitial tissues of the lungs, with a lack of effective therapies. Nobiletin is a polymethoxyflavonoid that exhibits characteristics of BH3 mimetics. It is mainly extracted from citrus peels and is known for its diverse pharmacological activities. Given the unsatisfactory clinical trial results of nintedanib, a combined treatment approach may represent a viable strategy for combating pulmonary fibrosis.

Methods

An in vitro pulmonary fibrosis model was established by inducing MRC-5 cells with transforming growth factor-β1 (TGF-β1). The impact of nobiletin combined with nintedanib on the migration of MRC-5 cells was assessed by wound healing and Transwell assays. Immunofluorescence and Western blot analyses were employed to assess the effect of drug combination on fibrosis-related markers, while Co-Immunoprecipitation (Co-IP) experiments were performed to assess the effects on autophagy. The anti-fibrotic effects and potential mechanisms of the combination of nobiletin and nintedanib were further explored using a bleomycin-induced pulmonary fibrosis model in C57BL/6 J mice.

Results

In vitro, the combination of nobiletin and nintedanib significantly inhibited MRC-5 cells' migration and extracellular matrix deposition, while simultaneously promoting apoptosis and autophagy. In addition, this combination exerted an anti-pulmonary fibrosis effect by regulating epigenetic mechanisms and the PI3K-AKT-mTOR signaling pathway. In vivo studies further revealed that the combination of nobiletin and nintedanib significantly reduced hydroxyproline levels in mice, attenuated lung inflammation, and helped to limit or prevent collagen accumulation.

Conclusions

Our study demonstrates that the combination of nobiletin and nintedanib exhibits promising anti-fibrotic effects both in vitro and in vivo.

背景：肺纤维化是一种众所周知的慢性进行性肺病，主要影响肺间质组织，缺乏有效的治疗方法。苦楝素是一种多甲氧基类黄酮，具有BH3模拟物的特性。它主要是从柑橘皮中提取的，以其多种药理活性而闻名。鉴于尼达尼布的临床试验结果不令人满意，联合治疗方法可能是对抗肺纤维化的可行策略。方法：采用转化生长因子-β1 （TGF-β1）诱导MRC-5细胞建立体外肺纤维化模型。nobiletin联合尼达尼布对MRC-5细胞迁移的影响通过伤口愈合和Transwell试验进行评估。采用免疫荧光和Western blot分析评估联合用药对纤维化相关标志物的影响，采用共免疫沉淀（Co-Immunoprecipitation, Co-IP）实验评估对自噬的影响。采用博莱霉素诱导C57BL/6 J小鼠肺纤维化模型，进一步探讨诺比莱素与尼达尼布联合抗纤维化作用及可能机制。结果：诺比莱素与尼达尼布联合在体外显著抑制MRC-5细胞的迁移和细胞外基质沉积，同时促进细胞凋亡和自噬。此外，该组合通过调节表观遗传机制和PI3K-AKT-mTOR信号通路发挥抗肺纤维化作用。体内研究进一步表明，诺biletin和尼达尼布联合使用可显著降低小鼠体内羟脯氨酸水平，减轻肺部炎症，并有助于限制或阻止胶原蛋白的积累。结论：我们的研究表明，诺匹莱素和尼达尼布联合使用在体内和体外都有很好的抗纤维化作用。

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引用次数: 0

The IL1β-NFκB-SDC4 signaling Axis promotes esophageal cancer cell proliferation and is suppressed by EGCG il - 1β- nfκ b - sdc4信号轴促进食管癌细胞增殖，受EGCG抑制

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-12 DOI: 10.1016/j.cellsig.2026.112365

Fei Zhou , Yuanduo Li , Xiaotong Liang , Xiaoru Xie , Wenzhang Zheng , Zikai Chen , Xianghui Zou , Zhicong Liu , Feng Pan , Hui Zhu , Yuzhong Zheng

Chronic inflammation promotes esophageal cancer (EC) progression through NFκB activation, yet the downstream effector genes driving EC progression remain incompletely characterized. Here, we identify syndecan-4 (SDC4) as a new NFκB target gene that is upregulated in EC and associated with poor prognosis. The pro-inflammatory cytokine IL1β stimulates EC cell proliferation and concurrently induces SDC4 expression in an NFκB-dependent manner. Mechanistically, NFκB directly binds to the SDC4 promoter region, which is enriched with the active chromatin marker H3K27Ac. Functional studies demonstrate that SDC4 is necessary for IL1β-driven proliferation, as its knockdown suppresses, whereas overexpression enhances EC cell proliferation. Notably, the natural compound epigallocatechin gallate (EGCG) effectively blocks this IL1β-NFκB-SDC4 axis by inhibiting NFκB nuclear translocation, thereby attenuating SDC4 upregulation and subsequent EC cell proliferation. Our findings establish SDC4 as a critical molecular link between inflammation and EC progression, and highlight EGCG as a potential therapeutic candidate targeting this pathway.

慢性炎症通过激活NFκB促进食管癌（EC）进展，但驱动EC进展的下游效应基因尚未完全确定。在这里，我们发现syndecan-4 （SDC4）是一个新的NFκB靶基因，在EC中上调并与不良预后相关。促炎细胞因子il - 1β刺激EC细胞增殖，同时以依赖nfκ b的方式诱导SDC4表达。在机制上，NFκB直接结合SDC4启动子区域，该区域富含活性染色质标记物H3K27Ac。功能研究表明，SDC4对于il - 1β驱动的增殖是必需的，因为它的敲低抑制，而过表达则增强EC细胞的增殖。值得注意的是，天然化合物表没食子儿茶素没食子酸酯（EGCG）通过抑制NFκB核易位有效阻断il - 1β-NFκB-SDC4轴，从而减弱SDC4上调和随后的EC细胞增殖。我们的研究结果表明SDC4是炎症和EC进展之间的关键分子联系，并强调EGCG是针对这一途径的潜在治疗候选药物。

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引用次数: 0

Dual-faced PUMA in CRC: A cytoplasmic autophagy repressor and mitochondrial mitophagy promoter 结直肠癌中的双面PUMA：细胞质自噬抑制因子和线粒体自噬启动因子。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-10 DOI: 10.1016/j.cellsig.2026.112363

Meimei Jiang , Mingyi Zhao , Yeying Liu , Jing Liu , Nannan Liu , Jiehan Li , Wunan Mi , Guiyun Jia , Yang Fu , Lingling Zhang , Yingjie Zhang , Feng Wang

As Bcl-2 family members, PUMA and Bcl-X_L played critical roles in mitochondrial apoptosis. However, whether they can regulate autophagy, especially mitophagy, is not understood at all. In this study, we explore the interaction among PUMA and Bcl-X_L in different subcellular localizations, and their functions in autophagy and mitophagy respectively. The detailed mechanisms were determined by mitochondria purification, Co-IP, and western blot analysis. Moreover, living cell imaging was performed to determine the occurrence of mitophagy. We found that PUMA inhibited autophagy by interacting with Ulk1 and Beclin1 in the cytoplasm. Six mutants of PUMA were constructed to further study which part is responsible for the interaction, and the BH3 domain shows indispensability. When PUMA moved to mitochondria and formed a complex with Ulk1 and Bcl-X_L, which played opposite roles, in promoting mitophagy. During this process, Ser96 of PUMA was indispensable for activating mitophagy. Besides, over-expressed PUMA or Bcl-X_L promotes obvious mitophagy, and the real-time detection of lysosome and mitochondria shows fusion. Our results identified new functions and molecular mechanisms of PUMA and Bcl-X_L in autophagy and mitophagy, which supplied theoretical bases for CRC therapy and other diseases.

PUMA和Bcl-XL作为Bcl-2家族成员，在线粒体凋亡过程中发挥重要作用。然而，它们是否能够调节自噬，特别是有丝自噬，目前还不清楚。在本研究中，我们探讨了PUMA和Bcl-XL在不同亚细胞定位中的相互作用，以及它们在自噬和有丝自噬中的作用。通过线粒体纯化、Co-IP和western blot分析确定了详细的机制。此外，通过活细胞成像来确定有丝分裂的发生。我们发现PUMA通过与细胞质中的Ulk1和Beclin1相互作用抑制自噬。我们构建了PUMA的6个突变体来进一步研究是哪个部分负责相互作用，BH3结构域是不可或缺的。当PUMA移动到线粒体并与Ulk1和Bcl-XL形成复合物时，它们在促进线粒体自噬中发挥相反的作用。在这个过程中，PUMA的Ser96对于激活有丝分裂是必不可少的。此外，过表达PUMA或Bcl-XL促进了明显的线粒体自噬，实时检测溶酶体和线粒体显示融合。我们的研究结果发现了PUMA和Bcl-XL在自噬和有丝自噬中的新功能和分子机制，为结直肠癌等疾病的治疗提供了理论依据。

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引用次数: 0

Role of CTRP9 in obesity-associated microglial dysregulation: Promoting lipophagy via the PI3K/AKT/FOXO1 signaling pathway CTRP9在肥胖相关小胶质细胞失调中的作用：通过PI3K/AKT/FOXO1信号通路促进脂肪吞噬。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-10 DOI: 10.1016/j.cellsig.2026.112358

Peng-Quan Chen , Ya-Dong Wei , Xin Zheng , Quan-Tong Xu , Song-Lin Xu , Shuai He , Meng-Jie Xu , Jin-Fang Ge

Activation of microglia triggers neuroinflammation, which subsequently leads to neurological dysfunction, representing a significant pathological mechanism underlying obesity-related cognitive impairment. Microglial lipophagy plays a critical role in regulating lipid homeostasis and inflammation; however, its involvement in obesity-related cognitive impairment remains largely unexplored. The accumulation of lipid droplets in microglia is a prominent feature of aging and reflects an imbalance in microglial lipid metabolism. CTRP9 is an important regulator in this process. The aim of this study was to investigate the potential role of CTRP9 in high-fat diet-induced disruption of microglial lipid metabolism. First, cognitive impairment was observed in an obesity model induced by a high-fat diet. We then observed a significant increase in lipid droplets in hippocampal microglia, inhibition of autophagic activity, and decreased CTRP9 expression in obese mice with cognitive impairment. Additionally, both BV2 and HMC3 cells stimulated with palmitic acid (PA) displayed lipid droplet accumulation, along with impaired lipophagy. Mechanistically, PA stimulation significantly reduced CTRP9 expression. To further investigate the role of CTRP9, we demonstrated that silencing CTRP9 exacerbated lipophagy impairment and increased lipid droplet accumulation in microglia. Conversely, overexpression of CTRP9 was able to reverse the aberrant activation of the PI3K/AKT/FOXO1 signaling pathway in PA-stimulated BV2 cells, thereby ameliorating these phenotypes. Taken together, these results suggest that CTRP9 plays a crucial regulatory role in lipid metabolism disorders in high-fat-stimulated microglia, and its mechanism may be closely linked to the dysfunction of the PI3K/AKT/FOXO1 signaling pathway.

小胶质细胞的激活引发神经炎症，随后导致神经功能障碍，这是肥胖相关认知障碍的重要病理机制。小胶质细胞脂质吞噬在调节脂质稳态和炎症中起关键作用；然而，它与肥胖相关的认知障碍的关系在很大程度上仍未被探索。小胶质细胞内脂滴的积累是衰老的一个突出特征，反映了小胶质细胞脂质代谢的不平衡。CTRP9在这个过程中是一个重要的调节因子。本研究的目的是研究CTRP9在高脂肪饮食诱导的小胶质细胞脂质代谢破坏中的潜在作用。首先，在高脂肪饮食引起的肥胖模型中观察到认知障碍。随后，我们观察到认知障碍肥胖小鼠海马小胶质细胞脂滴显著增加，自噬活性受到抑制，CTRP9表达降低。此外，在棕榈酸（PA）刺激下，BV2和HMC3细胞均表现出脂滴积聚，同时脂噬受损。在机制上，PA刺激显著降低CTRP9的表达。为了进一步研究CTRP9的作用，我们证明了沉默CTRP9会加剧小胶质细胞的脂噬损伤，增加脂滴积聚。相反，在pa刺激的BV2细胞中，CTRP9的过表达能够逆转PI3K/AKT/FOXO1信号通路的异常激活，从而改善这些表型。综上所述，这些结果表明CTRP9在高脂肪刺激的小胶质细胞脂质代谢紊乱中起着至关重要的调节作用，其机制可能与PI3K/AKT/FOXO1信号通路的功能障碍密切相关。

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引用次数: 0

Jagged1-Notch1/Foxo1 signaling crosstalk regulates TXNIP/NLRP3 inflammasome to alleviate lung inflammation Jagged1-Notch1/Foxo1信号串扰调控TXNIP/NLRP3炎性体减轻肺部炎症。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-10 DOI: 10.1016/j.cellsig.2026.112361

Tao Yang , Qianqian Jiang , Defei Tan , Hongfeng Yang , Yijun Shi , Junlan Zhou , Ying Li , Chenyang Liu , Lingling Li , Xin Yao , Qin Chen , Ying Zhou , Longfeng Jiang

Background

Notch signaling regulate innate immune cell function during tissue injury, while thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome activation drives lung inflammation. However, the role of Jagged1-mediated macrophage Notch1 signaling in regulating TXNIP/NLRP3 inflammasome function in lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear.

Methods

To investigate this, we utilized wild-type (WT), floxed Notch1 (Notch1^FL/FL) and myeloid-specific Notch1 knockout (Notch1^M−KO) mice were intratracheal instill LPS (5 mg/kg) to induce ALI. In some Notch1^M−KO mice, endogenous macrophage Foxo1 was knocked down using a Foxo1 siRNA mix combined with mannose-conjugated polymers before the LPS challenge. Primary AEC IIs from WT mice were transfected with CRISPR/Cas9-mediated Jagged1 knockout (KO) or Jagged1 activation (ACT) vector, challenged with LPS (100 ng/mL), and cocultured with bone marrow-derived macrophages (BMMs). BMMs from Notch1^M−KO mice were also obtained and transfected with CRISPR/Cas9-mediated Foxo1 knockout (KO) vector before subjected to LPS challenged.

Results

Herein, we discovered that recombinant Jagged1 administration in WT mice reduces LPS-induced ALI by promoting Notch signaling activation. Apoptotic AEC IIs release Jagged1, which activates Notch1 signaling in macrophages. Notably, myeloid-specific Notch1 deficiency exacerbates LPS-induced inflammation response and oxidative stress, accompanied by elevated Foxo1 and dysregulated TXNIP/NLRP3 activity. Mechanistically, Notch intracellular domain (NICD) and Foxo1 colocalized in the nucleus, where Foxo1 competed with NICD for RBP-Jκ binding, impairing Notch1 signaling and promoting inflammasome activation. Importantly, Foxo1 deletion in macrophages rescued these effects.

Conclusions

Collectively, we characterized a novel molecular mechanism involving the Jagged1-Notch1-Foxo1 axis in regulating the TXNIP/NLRP3 pathway, which is dysregulated in ALI. These findings highlight the potential of targeting this pathway for therapeutic intervention in ALI.

背景：在组织损伤过程中，Notch信号调节先天免疫细胞功能，而硫氧还蛋白相互作用蛋白(TXNIP)/ nod样受体蛋白3 （NLRP3）炎症小体激活驱动肺部炎症。然而，在脂多糖（LPS）诱导的急性肺损伤（ALI）中，jagged1介导的巨噬细胞Notch1信号在调节TXNIP/NLRP3炎性体功能中的作用尚不清楚。方法：采用野生型（WT）、含绒Notch1 （Notch1FL/FL）和骨髓特异性Notch1敲除（Notch1M-KO）小鼠气管内灌注LPS（5 mg/kg）诱导ALI。在一些Notch1M-KO小鼠中，内源性巨噬细胞Foxo1在LPS刺激前被Foxo1 siRNA混合物与甘露糖偶联聚合物联合敲低。用CRISPR/ cas9介导的Jagged1敲除（KO）或Jagged1激活（ACT）载体转染WT小鼠的AEC ii，用LPS（100 ng/mL）激发，并与骨髓源性巨噬细胞（BMMs）共培养。获得Notch1M-KO小鼠的bmm，用CRISPR/ cas9介导的Foxo1敲除（KO）载体转染，然后进行LPS刺激。结果：我们发现重组Jagged1在WT小鼠中通过促进Notch信号激活来减少lps诱导的ALI。凋亡的AEC ii释放Jagged1，激活巨噬细胞的Notch1信号。值得注意的是，骨髓特异性Notch1缺陷加剧了lps诱导的炎症反应和氧化应激，并伴有Foxo1升高和TXNIP/NLRP3活性失调。在机制上，Notch胞内结构域（NICD）和Foxo1共定位于细胞核，Foxo1与NICD竞争RBP-Jκ结合，损害Notch1信号传导并促进炎症小体激活。重要的是，巨噬细胞中的Foxo1缺失恢复了这些作用。结论：总的来说，我们发现了一种新的分子机制，涉及Jagged1-Notch1-Foxo1轴调节在ALI中失调的TXNIP/NLRP3通路。这些发现强调了针对这一途径进行ALI治疗干预的潜力。

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引用次数: 0

Ophiopogonis japonicus polysaccharide inhibits oxidative stress in hepatocytes by promoting Runx3 in nonalcoholic fatty liver disease 麦冬多糖通过促进Runx3在非酒精性脂肪肝中抑制肝细胞氧化应激。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-09 DOI: 10.1016/j.cellsig.2026.112360

Xiuchun Zhang , Jianying Feng , Jie Zhou , Jian Wang , Yang Yang

Nonalcoholic fatty liver disease (NAFLD) represents the most prevalent chronic liver disease, yet there remains an unmet need for effective therapeutic interventions. This study aimed to investigate the hepatoprotective effect of Ophiopogonis japonicus polysaccharides (OJPs) on NAFLD and its mechanism. The benefits of OJPs or the positive drug fenofibrate in NAFLD were assessed in mice fed a high-fat diet (HFD). AML12 cells were induced with PA/OA to construct an in vitro model, and the benefits of OJPs were assessed in terms of oil red O staining, BODIPY staining, changes in the expression of lipid accumulation-related proteins, iron metabolism-related proteins, and oxidative stress analysis. OJPs significantly alleviated lipid accumulation and oxidative stress in PA/OA-induced AML12 cells, and maintained iron metabolism in the liver of HFD-induced mice, but the benefits of OJPs were reversed after exogenous inhibition of Runt-related transcription factor 3 (Runx3). More importantly, knockdown of Runx3 combined with overexpression of ATP-binding cassette transporter 7 (Abcb7) again restored the benefit of OJPs. Runx3 transcriptionally activated Abcb7 by binding to its promoter. The findings suggest that OJPs could serve as a pharmaceutical intervention for NAFLD through the Runx3/Abcb7 axis. This discovery unveils an unexplored association between iron metabolism and hepatic disease.

非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，但对有效治疗干预的需求仍未得到满足。本研究旨在探讨麦冬多糖（OJPs）对NAFLD的保肝作用及其机制。在喂食高脂肪饮食（HFD）的小鼠中，评估了OJPs或阳性药物非诺贝特对NAFLD的益处。用PA/OA诱导AML12细胞构建体外模型，通过油红O染色、BODIPY染色、脂质积累相关蛋白、铁代谢相关蛋白表达变化及氧化应激分析评估OJPs的益处。OJPs可显著缓解PA/ oa诱导的AML12细胞的脂质积累和氧化应激，维持hfd诱导小鼠肝脏中的铁代谢，但在外源性抑制runt相关转录因子3 （Runx3）后，OJPs的益处被逆转。更重要的是，Runx3的敲低与atp结合盒转运体7 （Abcb7）的过表达再次恢复了ojp的益处。Runx3通过结合Abcb7的启动子转录激活Abcb7。研究结果表明，OJPs可以通过Runx3/Abcb7轴作为NAFLD的药物干预。这一发现揭示了铁代谢与肝脏疾病之间未被探索的联系。

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引用次数: 0

The Limb-bud and Heart (LBH) promotes renal fibrosis through endoplasmic reticulum stress-induced pyroptosis and partial epithelial-mesenchymal transition in renal tubular epithelial cells 肢体芽和心脏（LBH）通过内质网应激诱导的焦亡和肾小管上皮细胞部分上皮-间质转化促进肾纤维化。

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-09 DOI: 10.1016/j.cellsig.2026.112359

Tao Shu , Ning Luo , Yuqi Shu , Jingyan Wei , Hongxin Niu , Qicai Liu

Renal fibrosis is a primary pathological feature of chronic kidney disease, with a current lack of effective treatments. In this study, we observed that Limb-bud and Heart (LBH) expression was upregulated in kidney specimens obtained from patients with chronic kidney disease. During UUO-induced renal fibrosis, both the protein level and mRNA level of LBH were significantly elevated. Furthermore, knockout of the mouse LBH gene significantly ameliorated renal fibrosis. The application of inhibitors, agonists, and knockout mouse models uniformly verified the role of LBH deficiency in alleviating both endoplasmic reticulum stress (ERS) and pyroptosis. Although renal tubular epithelial cells (RTECs) are conventionally considered the initial responders to renal fibrosis, the role and mechanism of LBH in these cells during disease progression remain unclear. Therefore, this study focused on investigating LBH's effects in damaged RTECs. Mechanistic studies demonstrated that within renal tubular epithelial cells, LBH significantly promotes renal fibrosis by forming a positive feedback loop with TGFβ1 and ERS. This activated ERS subsequently further induces pyroptosis and partial epithelial-mesenchymal transition (pEMT), thereby promoting renal fibrosis. Importantly, LBH deficiency was shown to significantly attenuate renal fibrosis. These collective findings strongly suggest that LBH may constitute a promising therapeutic target for the treatment of renal fibrosis.

肾纤维化是慢性肾脏疾病的主要病理特征，目前缺乏有效的治疗方法。在这项研究中，我们观察到从慢性肾病患者的肾脏标本中获得的肢体芽和心脏（LBH）表达上调。在uuo诱导的肾纤维化过程中，LBH蛋白水平和mRNA水平均显著升高。此外，敲低小鼠LBH基因可显著改善肾纤维化。抑制剂、激动剂和敲除小鼠模型的应用一致证实了LBH在缓解内质网应激（ERS）和焦死方面的作用。尽管肾小管上皮细胞（RTECs）通常被认为是肾纤维化的初始应答者，但LBH在疾病进展过程中在这些细胞中的作用和机制尚不清楚。因此，本研究的重点是研究LBH对受损rtec的影响。机制研究表明，在肾小管上皮细胞内，LBH通过与tgf - β1和ERS形成正反馈回路，显著减轻肾纤维化。这种激活的ERS随后进一步诱导焦亡和部分上皮-间质转化（ppt），从而促进肾纤维化。重要的是，LBH缺乏被证明可以显著减轻肾纤维化。这些共同的发现强烈表明，LBH可能是治疗肾纤维化的一个有希望的治疗靶点。

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引用次数: 0

The role of insulin-like growth factor binding proteins in TGF-β1-induced fibroblast-myofibroblast transition during endometriosis fibrosis 胰岛素样生长因子结合蛋白在TGF-β1诱导的子宫内膜异位症纤维化过程中成纤维细胞-肌成纤维细胞转化中的作用

IF 3.7 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2026-01-09 DOI: 10.1016/j.cellsig.2026.112362

Xianglian Wang , Jia He , Simeng Shen , Manwei Li , Siyi Yuan , Wei Xu , Shu Zhu , Yan Ding , Xiuli Wang

Fibrosis is a defining feature of endometriosis (EMS). Our previous single-cell RNA sequencing (scRNA-seq) revealed myofibroblasts (MFBs) as the predominant cells in ectopic endometrium (ECE), mainly derived from fibroblast-to-myofibroblast transition (FMT) driven by transforming growth factor (TGF)-β pathways. Insulin-like growth factor binding proteins (IGFBPs), known regulators of fibrosis in other diseases, remain unexplored in EMS. This study investigated the role of IGFBPs in TGF-β1-induced FMT during EMS-associated fibrosis. We found that elevated TGF-β1 and TGF-βR1 in the EMS microenvironment promoted MFB formation via Smad2/3 and ERK1/2 signaling. IGFBP1 and IGFBP2 were upregulated, whereas IGFBP6 was downregulated in ectopic endometrial stromal cells (EcESCs), and all interacted with TGF-β1. Importantly, IGFBP6 suppressed TGF-β1-induced FMT and fibrosis. This is the first study to define the role of IGFBPs in EMS fibrosis, highlighting IGFBP6 as a potential antifibrotic factor and therapeutic target.

纤维化是子宫内膜异位症（EMS）的一个决定性特征。我们之前的单细胞RNA测序（scRNA-seq）显示，肌成纤维细胞（MFBs）是异位子宫内膜（ECE）的主要细胞，主要来源于转化生长因子(TGF)-β途径驱动的成纤维细胞向肌成纤维细胞转化（FMT）。胰岛素样生长因子结合蛋白（igfbp）是其他疾病中已知的纤维化调节因子，但在EMS中仍未被发现。本研究探讨了igfbp在ems相关纤维化过程中TGF-β1诱导的FMT中的作用。我们发现，EMS微环境中TGF-β1和TGF-βR1的升高通过Smad2/3和ERK1/2信号通路促进MFB的形成。异位子宫内膜基质细胞（EcESCs）中IGFBP1和IGFBP2表达上调，IGFBP6表达下调，且均与TGF-β1相互作用。重要的是，IGFBP6抑制TGF-β1诱导的FMT和纤维化。这是第一个明确igfbp在EMS纤维化中的作用的研究，强调了IGFBP6作为潜在的抗纤维化因子和治疗靶点。

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引用次数: 0