Cell Death & Disease最新文献_第2页

HMGB1 orchestrates tumor-osteoclast crosstalk to drive bone metastasis in hepatocellular carcinoma. HMGB1调控肿瘤-破骨细胞串扰，驱动肝癌骨转移。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-07 DOI: 10.1038/s41419-025-08037-6

Yan-Zhu Chen, Di Xu, Ya-Xun Jia, Jie Ma, Zuo-Lin Xiang

{"title":"HMGB1 orchestrates tumor-osteoclast crosstalk to drive bone metastasis in hepatocellular carcinoma.","authors":"Yan-Zhu Chen, Di Xu, Ya-Xun Jia, Jie Ma, Zuo-Lin Xiang","doi":"10.1038/s41419-025-08037-6","DOIUrl":"10.1038/s41419-025-08037-6","url":null,"abstract":"Bone metastasis in hepatocellular carcinoma (HCC) poses a significant clinical challenge, characterized by poor prognosis and severe skeletal complications. This study identifies the HMGB1/LCN2/JAK1/STAT3 axis as the central mechanism driving HCC bone metastasis through tumor-osteoclast crosstalk. High-mobility group box 1 (HMGB1) induces osteoclast activation and differentiation, promoting lipocalin-2 (LCN2) secretion by osteoclasts, which activates the JAK1/STAT3 pathway in HCC cells, forming a feedback loop that enhances osteolytic bone resorption and tumor dissemination. Integrated single-cell and bulk RNA sequencing reveal enriched osteoclast-related and pro-metastatic pathways in the tumor-bone microenvironment, while functional assays involving knockdown and overexpression demonstrate that modulating the HMGB1/LCN2/JAK1/STAT3 axis regulates osteoclast activity, tumor growth, and bone destruction in vitro and in vivo. These results suggest the HMGB1/LCN2/JAK1/STAT3 axis as a potential therapeutic target, offering a strategy to reduce skeletal damage and systemic tumor progression, thereby contributing to improved management of advanced HCC.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"712"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ADAP-METTL3 modulates the inflammatory responses of macrophages via m⁶A modification of Spry1. ADAP-METTL3通过m6A修饰Spry1来调节巨噬细胞的炎症反应。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-07 DOI: 10.1038/s41419-025-08008-x

Anqi Dong, Pengchao Zhang, Fan Yang, Yanqi Wang, Hebin Liu

{"title":"ADAP-METTL3 modulates the inflammatory responses of macrophages via m6A modification of Spry1.","authors":"Anqi Dong, Pengchao Zhang, Fan Yang, Yanqi Wang, Hebin Liu","doi":"10.1038/s41419-025-08008-x","DOIUrl":"10.1038/s41419-025-08008-x","url":null,"abstract":"While N6-methyladenosine (m6A) RNA modification is implicated in macrophage inflammatory responses, its regulatory mechanisms remain elusive. Our prior studies demonstrated that a deficiency in the immune adaptor protein ADAP promotes inflammation in TLR4-stimulated macrophages. Here, we show that ADAP binds to METTL3, and depletion of Mettl3 alleviates the hyperinflammation in Adap-/- macrophages, indicating METTL3 counteracts the anti-inflammatory function of ADAP in macrophages. Furthermore, LPS induces the METTL3-dependent m6A methylation of Spry1 mRNA in macrophages in the A6988 within the motif GGACU, which is further potentiated upon the depletion of ADAP. Moreover, this positive effect of ADAP deficiency on LPS-induced m6A methylation of Spry1 mRNA is dependent on IGF2BP2, which specifically binds to and stabilize the m6A modified Spry1 mRNA that contributes to an exacerbation of the inflammation in Adap-/- macrophages via NF-κB activation in macrophages. Together, our findings unveil a reciprocal inhibition between ADAP and METTL3 that fine-tunes the inflammatory responses of macrophages via modulation of the m6A methylation of Spry1 mRNA.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"708"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fatty acid synthase-mediated lipid droplet formation enhances macrophage killing of Staphylococcus aureus. 脂肪酸合酶介导的脂滴形成增强巨噬细胞对金黄色葡萄球菌的杀伤作用。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-07 DOI: 10.1038/s41419-025-08044-7

Yanping Wu, Jiaxin Shen, Shenwei Gao, Miao Li, Qingyu Weng, Kua Zheng, Chen Zhu, Zhongnan Qin, Jieyu Li, Jiafei Lou, Songmin Ying, Yinfang Wu, Zhihua Chen, Wen Li

{"title":"Fatty acid synthase-mediated lipid droplet formation enhances macrophage killing of Staphylococcus aureus.","authors":"Yanping Wu, Jiaxin Shen, Shenwei Gao, Miao Li, Qingyu Weng, Kua Zheng, Chen Zhu, Zhongnan Qin, Jieyu Li, Jiafei Lou, Songmin Ying, Yinfang Wu, Zhihua Chen, Wen Li","doi":"10.1038/s41419-025-08044-7","DOIUrl":"10.1038/s41419-025-08044-7","url":null,"abstract":"Macrophages play a critical role in defending against Staphylococcus aureus (S. aureus), a major human pathogen. Recently, there has been growing interest in the metabolic regulation of macrophage function; however, the specific role of lipid synthesis in macrophage activation remains poorly understood. This study demonstrates that fatty acid synthase (FASN), an enzyme integral to de novo lipogenesis, is significantly upregulated in macrophages during S. aureus infection. Notably, S. aureus engages in a functional interaction with proteasomes, inhibiting their activity through the PI3K/AKT/mTOR signaling pathway. This interaction results in reduced degradation of FASN, leading to elevated levels of this crucial enzyme. The increased expression of FASN is vital for macrophage-mediated pathogen clearance, as it facilitates the formation of lipid droplets (LDs), which in turn enhance the antimicrobial response against S. aureus, partly through the accumulation of the antimicrobial peptide CAMP. In a murine pneumonia model, deficiency of FASN correlates with increased bacterial burden, exacerbated lung inflammation, and a significant reduction in survival rates. Collectively, these findings underscore the essential role of FASN-mediated LD formation in macrophage activation and highlight potential therapeutic targets within the FASN and lipid metabolism pathways for the treatment of S. aureus pneumonia.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"715"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IRE1α translational suppression potentiates STING-dependent chemoresistance in pancreatic cancer. IRE1α翻译抑制增强胰腺癌sting依赖性化疗耐药

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-06 DOI: 10.1038/s41419-025-07999-x

Yuan Luo, Mengqi Sun, Lei Chang, Zinan He, Xinghang Zhou, Yaming Yuan, Huijuan Sun, Shiqi Luo, Jinyan Huang, Hongkun Wu, Wenjun Liu, Zhangsen Zhou, Yuanhui Mao, Yewei Ji, Tingbo Liang

{"title":"IRE1α translational suppression potentiates STING-dependent chemoresistance in pancreatic cancer.","authors":"Yuan Luo, Mengqi Sun, Lei Chang, Zinan He, Xinghang Zhou, Yaming Yuan, Huijuan Sun, Shiqi Luo, Jinyan Huang, Hongkun Wu, Wenjun Liu, Zhangsen Zhou, Yuanhui Mao, Yewei Ji, Tingbo Liang","doi":"10.1038/s41419-025-07999-x","DOIUrl":"10.1038/s41419-025-07999-x","url":null,"abstract":"Chemotherapy remains a standard treatment for pancreatic ductal adenocarcinoma (PDAC); however, its effectiveness is limited, and the underlying mechanisms are poorly understood. STING plays diverse and critical roles in cancer, yet the role of PDAC cell-intrinsic STING signaling and its regulation under chemotherapy remain unclear. Here, we report that chemotherapy induces cancer cell-intrinsic STING signaling and that STING deletion in PDAC enhances cell death under chemotherapy while suppressing tumor growth in both immune-deficient and immune-competent mice. Interestingly, chemotherapy selectively inhibits translation of IRE1α, an ER membrane protein and a canonical mediator of ER stress. Loss of IRE1α in PDAC amplifies STING signaling and increases resistance to chemotherapy. Mechanistically, IRE1α interacts with STING via their transmembrane regions, reducing STING stability in PDAC cells. Our study reveals that PDAC cells downregulate IRE1α to reinforce STING-mediated pro-survival response; however, this adaptation also makes them more vulnerable to proteostasis imbalance and ER stress-induced cell death. Notably, we demonstrate that combining ER stress inducers with STING signaling inhibition enhances chemotherapy efficacy both in vitro and in vivo.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"680"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human immunodeficiency virus 1 glycoprotein 120 induces endoplasmic reticulum stress in neurons. 人类免疫缺陷病毒1糖蛋白120诱导神经元内质网应激。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-06 DOI: 10.1038/s41419-025-08032-x

Christy Agbey, Lee A Campbell, Thieu Phan, Gerard Ahern, Italo Mocchetti

{"title":"Human immunodeficiency virus 1 glycoprotein 120 induces endoplasmic reticulum stress in neurons.","authors":"Christy Agbey, Lee A Campbell, Thieu Phan, Gerard Ahern, Italo Mocchetti","doi":"10.1038/s41419-025-08032-x","DOIUrl":"10.1038/s41419-025-08032-x","url":null,"abstract":"People living with Human Immunodeficiency Virus (HIV) (PLWH) may develop HIV-associated neurocognitive disorder (HAND) despite the use of antiretroviral therapy. Therefore, more studies are needed to identify novel therapies, which require a better understanding of the molecular and cellular mechanisms underlying HIV neurotoxicity. The HIV envelope protein gp120 causes neuronal degeneration similar to that observed in HAND. One mechanism contributing to gp120-mediated neurotoxicity may involve its ability to inhibit protein processing in the Golgi apparatus and endoplasmic reticulum (ER). To provide data in support to this hypothesis, we have used a variety of experimental approaches to investigate the effect of gp120 on ER dynamics. We first analyzed the levels of ER stress-associated proteins, such as immunoglobulin heavy chain binding protein (BiP) and phosphorylated Inositol-Requiring Enzyme 1 alpha (p-IRE1α) by western blot, as well as ER morphology by electron microscopy in gp120 transgenic (tg) mice. We found that the hippocampus of gp120tg mice exhibits an increase of BiP levels and p-IRE1α, as well as altered ER morphology when compared to wild type mice. We confirmed that gp120 alters ER morphology in neurons by using rat cortical neurons in culture. The effect of gp120 was chemokine-co-receptor dependent because AMD3100, a CXCR4 receptor antagonist, abolished the effect of gp120 on BiP immunoreactivity. Moreover, using Gluc-ASARTDL, a reporter protein for monitoring ER calcium, and live Ca2+ imaging, we show that gp120 induces ER Ca2+ depletion in neurons. Overall, our data suggest that gp120 promotes ER stress in neurons.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"704"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transferrin is a drug candidate for the treatment of dry age-related macular degeneration (AMD). 转铁蛋白是治疗干性年龄相关性黄斑变性（AMD）的候选药物。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-06 DOI: 10.1038/s41419-025-07950-0

Jenny Youale, Karine Bigot, Thara Jaworski, Cécile Lebon, Anaïs Françon, Kimberley Delaunay, Romain Bénard, Thaïs De Bastard, Alejandra Daruich, Naël Kaddour, Thierry Bordet, Francine Behar-Cohen, Emilie Picard

{"title":"Transferrin is a drug candidate for the treatment of dry age-related macular degeneration (AMD).","authors":"Jenny Youale, Karine Bigot, Thara Jaworski, Cécile Lebon, Anaïs Françon, Kimberley Delaunay, Romain Bénard, Thaïs De Bastard, Alejandra Daruich, Naël Kaddour, Thierry Bordet, Francine Behar-Cohen, Emilie Picard","doi":"10.1038/s41419-025-07950-0","DOIUrl":"10.1038/s41419-025-07950-0","url":null,"abstract":"Dysregulation of iron homeostasis plays a crucial role in retinal diseases, contributing to oxidative stress, inflammation, and ferroptosis, key processes that drive the degeneration of the retinal pigment epithelium (RPE) and photoreceptors in age-related macular degeneration (AMD). Previous studies, though limited in patient numbers, have reported elevated iron levels in the aqueous humor, RPE, and Bruch's membrane of AMD patients. In this study, we aimed to confirm iron imbalance in a larger cohort of AMD patients and assess its correlation with disease stage. Elevated iron levels and a reduction in transferrin (TF) iron-binding capacity were observed in patients with early geographic atrophy (GA). RPE cells derived from human stem cells exhibited AMD-like features when exposed to iron overload or oxidized lipids. Treatment with TF appeared to restore aspects of iron homeostasis and reduce oxidative stress, mitochondrial damage, inflammation, complement activation, and ferroptosis in this model. These findings suggest that TF supplementation may represent a potential therapeutic strategy to help prevent or slow AMD progression.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"692"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acetylation-dependent USP7-TRIM25 axis drives oncogenic progression in non-small cell lung cancer. 乙酰化依赖性USP7-TRIM25轴驱动非小细胞肺癌的癌性进展。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-06 DOI: 10.1038/s41419-025-08034-9

Jian Yang, Zhike Chen, Wenxuan Hu, Weibiao Zeng, Zhe Lei, Xin Tong, Qifan Li, Gaomeng Luo, Kang Hu, Zhimeng Chen, Zeyi Liu, Chang Li, Chun Xu, Cheng Ding, Hong-Tao Zhang, Jun Zhao

{"title":"Acetylation-dependent USP7-TRIM25 axis drives oncogenic progression in non-small cell lung cancer.","authors":"Jian Yang, Zhike Chen, Wenxuan Hu, Weibiao Zeng, Zhe Lei, Xin Tong, Qifan Li, Gaomeng Luo, Kang Hu, Zhimeng Chen, Zeyi Liu, Chang Li, Chun Xu, Cheng Ding, Hong-Tao Zhang, Jun Zhao","doi":"10.1038/s41419-025-08034-9","DOIUrl":"10.1038/s41419-025-08034-9","url":null,"abstract":"Tripartite motif containing 25 (TRIM25), an E3 ubiquitin ligase that plays an important role in bioprocesses, is frequently elevated in malignant tumors. However, it remains unclear how TRIM25 protein expression is regulated in non-small cell lung cancer (NSCLC). Here, we find that TRIM25 is hyper-expressed in NSCLC tissues and associated with poor prognosis of NSCLC patients. Both in vitro and in vivo experiments indicate that TRIM25 facilitates tumor proliferation and metastasis. Mechanistically, acetylation is identified as a critical post-translational modification (PTM) regulating TRIM25 protein stability in NSCLC. The lysine acetyltransferase cAMP-responsive element-binding (CREB)-binding protein (CBP) mediates acetylation of TRIM25 at lysine 392, which is counteracted by the deacetylase Sirtuin 7 (SIRT7). Notably, the acetylation of TRIM25 enhances its interaction with ubiquitin specific peptidase 7 (USP7), resulting in reduced ubiquitination of TRIM25. In summary, our study reveals a novel acetylation modification site, thus providing new insights into an epigenetic regulation of TRIM25 in human cancer, and suggesting that pharmacological inhibition of TRIM25 acetylation is a potential anti-tumor strategy.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"695"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NY-ESO-1 facilitates anoikis resistance and tumor metastasis by hijacking deubiquitinase OTUB1 to stabilize PP1α. NY-ESO-1通过劫持去泛素酶OTUB1来稳定PP1α，促进anoikis耐药和肿瘤转移。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-06 DOI: 10.1038/s41419-025-08017-w

Pengchao Zhang, Jian Cheng, Zhao Liu, Funmilayo O Adeshakin, Liujiang Dai, Xiangyun Niu, Ziyang Zhang, Xixia Peng, Long Li, Maoxuan Liu, Dehong Yan, Xiaolu Yang, Xiaochun Wan, Guizhong Zhang

{"title":"NY-ESO-1 facilitates anoikis resistance and tumor metastasis by hijacking deubiquitinase OTUB1 to stabilize PP1α.","authors":"Pengchao Zhang, Jian Cheng, Zhao Liu, Funmilayo O Adeshakin, Liujiang Dai, Xiangyun Niu, Ziyang Zhang, Xixia Peng, Long Li, Maoxuan Liu, Dehong Yan, Xiaolu Yang, Xiaochun Wan, Guizhong Zhang","doi":"10.1038/s41419-025-08017-w","DOIUrl":"10.1038/s41419-025-08017-w","url":null,"abstract":"Anoikis resistance, an essential prerequisite for tumor metastasis, is now recognized as a promising target in the fight against tumor progression. However, the detailed mechanisms of anoikis resistance are not fully understood, and drugs targeting anoikis resistance are not currently available. Here we report that NY-ESO-1, a well-known cancer-testis antigen, is linked to a poor prognosis in tumor patients and that it is crucial for anoikis resistance and tumor metastasis. Overexpression of NY-ESO-1 in cancer cells enhanced ERK1/2 activation, which in turn promoted resistance to anoikis, increased colony formation in soft agar, and facilitated lung metastasis in mice. Conversely, NY-ESO-1 knockdown significantly reduced ERK1/2 activity, leading to enhanced anoikis, diminished colony formation, and impaired metastatic potential. Mechanistically, NY-ESO-1 acts as a scaffold protein to recruit the deubiquitinase OTUB1 to PP1α, forming a ternary complex that prevents PP1α from being ubiquitinated. The OTUB1's deubiquitinase activity, not its ability to suppress E2 enzymes, is necessary for reducing polyubiquitination and improving PP1α stability. Finally, accumulated PP1α proteins significantly activate downstream ERK1/2. Blockade of ERK1/2 or knocking down PP1α antagonized NY-ESO-1-mediated anoikis resistance. These results not only reveal a previously unrecognized mode for deubiquitinase substrate expansion but also highlight the function of NY-ESO-1 in anoikis resistance and suggest NY-ESO-1 as a novel attractive target for preventing tumor metastasis.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"682"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SDC4 drives fibrotic remodeling of the intervertebral disc under altered spinal loading. 在改变的脊柱负荷下，SDC4驱动椎间盘的纤维化重塑。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-06 DOI: 10.1038/s41419-025-08002-3

Kimheak Sao, Makarand V Risbud

{"title":"SDC4 drives fibrotic remodeling of the intervertebral disc under altered spinal loading.","authors":"Kimheak Sao, Makarand V Risbud","doi":"10.1038/s41419-025-08002-3","DOIUrl":"10.1038/s41419-025-08002-3","url":null,"abstract":"Alterations in physiological loading of the spine are deleterious to intervertebral disc health. The base of the mouse caudal spine region Ca3-6 that naturally experiences increased flexion, showed adaptive tissue remodeling, reminiscent of disc degeneration in young adult mice. Given the role of Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan in disc matrix turnover and mechanosensing, we investigated if deletion could mitigate this loading-dependent phenotype. Notably, at spinal levels Ca3-6, Sdc4-knockout (KO) mice did not exhibit increased collagen fibril and fibronectin deposition in the nucleus pulposus (NP) compartment or showed the alterations in collagen crosslinks observed in wild-type mice. Similarly, unlike wild-type mice, NP cells in Sdc4-KO mice retained transgelin (TAGLN) expression and showed absence of collagen type X (COL10) deposition, pointing to the preservation of their notochordal characteristics. Proteomic analysis revealed that NP tissues responded to the altered loading by increasing the abundance of proteins associated with extracellular matrix remodeling, chondrocyte development, and contractility. Similarly, downregulated proteins suggested decreased vesicle transport, autophagy-related pathway, and RNA quality control regulation. Notably, NP proteome from Sdc4-KO suggested that increased dynamin-mediated endocytosis, autophagy-related pathway, and RNA and DNA quality control may underscore the protection from adaptive tissue remodeling caused by this naturally observed altered loading. Our study highlights the important role of SDC4 in fine-tuning cellular homeostasis and extracellular matrix production in disc environment subjected to altered loading.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"678"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The IGF2BP3-FASN axis drives lipid metabolic reprogramming to promote brain colonization in non-small cell lung cancer. IGF2BP3-FASN轴驱动脂质代谢重编程，促进非小细胞肺癌的脑定植。

IF 9.6 1区生物学

Cell Death & Disease Pub Date : 2025-10-06 DOI: 10.1038/s41419-025-08006-z

Jingwei Li, Shumin Ouyang, Ziyou Lin, Keren Peng, Jiayu Yan, Minyuan Lu, Wen Ding, Jianshan Mo, Yingxue Su, Libin Wang, Peibin Yue, Jin-Jian Lu, Xiangchao Yao, Yandong Wang, Xiaolei Zhang

{"title":"The IGF2BP3-FASN axis drives lipid metabolic reprogramming to promote brain colonization in non-small cell lung cancer.","authors":"Jingwei Li, Shumin Ouyang, Ziyou Lin, Keren Peng, Jiayu Yan, Minyuan Lu, Wen Ding, Jianshan Mo, Yingxue Su, Libin Wang, Peibin Yue, Jin-Jian Lu, Xiangchao Yao, Yandong Wang, Xiaolei Zhang","doi":"10.1038/s41419-025-08006-z","DOIUrl":"10.1038/s41419-025-08006-z","url":null,"abstract":"Brain metastases represent a significant cause of morbidity and mortality in non-small cell lung cancer (NSCLC), with limited therapeutic options. The unique brain microenvironment, characterized by low lipid availability, may drive NSCLC cells to adapt through lipid metabolic reprogramming. In this study, we identify a novel mechanism by which IGF2BP3-driven lipid metabolism promotes the brain colonization of NSCLC cells through the IGF2BP3-FASN axis. Elevated IGF2BP3 expression in NSCLC brain metastases correlates with poor prognosis and promotes cancer cell migration, invasion, and brain colonization by activating the lipogenesis pathway. We further identified that FASN was a downstream target of IGF2BP3 in NSCLC cells. Mechanistically, IGF2BP3 binds to FASN mRNA, enhancing its stability through RNA-binding activity. FASN is essential for neutral lipid accumulation and brain colonization, as demonstrated in vitro and in vivo. Our findings highlight the critical role of IGF2BP3 in lipid metabolism and propose that targeting IGF2BP3 may provide a promising therapeutic strategy for NSCLC brain colonization.","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"684"},"PeriodicalIF":9.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12501377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0