Journal of Clinical Investigation最新文献_第10页

TRIB3 mediates vascular calcification through facilitating self-ubiquitination and dissociation of Smurf1 in chronic renal disease.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-11 DOI: 10.1172/JCI175972

Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong

{"title":"TRIB3 mediates vascular calcification through facilitating self-ubiquitination and dissociation of Smurf1 in chronic renal disease.","authors":"Yihui Li, Chang Ma, Yanan Sheng, Shanying Huang, Huaibing Sun, Yun Ti, Zhihao Wang, Feng Wang, Fangfang Chen, Chen Li, Haipeng Guo, Mengxiong Tang, Fangqiang Song, Hao Wang, Ming Zhong","doi":"10.1172/JCI175972","DOIUrl":"https://doi.org/10.1172/JCI175972","url":null,"abstract":"The osteogenic environment promotes vascular calcium phosphate deposition and aggregation of unfolded and misfolded proteins, resulting in endoplasmic reticulum (ER) stress in chronic renal disease (CKD). Controlling ER stress through genetic intervention is a promising approach for treating vascular calcification. In this study, we demonstrated a positive correlation between ER stress-induced tribble 3 (TRIB3) expression and progression of vascular calcification in human and rodent CKD. Increased TRIB3 expression promoted vascular smooth muscle cell (VSMC) calcification by interacting with the C2 domain of the E3 ubiquitin-protein ligase Smurf1, facilitating its K48-related self-ubiquitination at Lys381 and Lys383 and subsequent dissociation from the plasma membrane and nuclei. This degeneration of Smurf1 accelerated the stabilization of the osteogenic transcription factors RUNX Family Transcription Factor 2 (Runx2) and SMAD Family Member 1 (Smad1). C/EBP homologous protein and activating transcription factor 4 are upstream transcription factors of TRIB3 in an osteogenic environment. Genetic knockout of TRIB3 or rescue of Smurf1 ameliorated VSMC and vascular calcification by stabilizing Smurf1 and enhancing the degradation of Runx2 and Smad1. Our findings shed light on the vital role of TRIB3 as a scaffold in ER stress and vascular calcification and offer a potential therapeutic option for chronic renal disease.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RNase L represses hair follicle regeneration through altered innate immune signaling.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-04 DOI: 10.1172/JCI172595

Charles S Kirby, Nasif Islam, Eric Wier, Martin P Alphonse, Evan Sweren, Gaofeng Wang, Haiyun Liu, Dongwon Kim, Ang Li, Sam S Lee, Andrew M Overmiller, Yingchao Xue, Sashank Reddy, Nathan K Archer, Lloyd S Miller, Jianshi Yu, Weiliang Huang, Jace W Jones, Sooah Kim, Maureen A Kane, Robert H Silverman, Luis A Garza

{"title":"RNase L represses hair follicle regeneration through altered innate immune signaling.","authors":"Charles S Kirby, Nasif Islam, Eric Wier, Martin P Alphonse, Evan Sweren, Gaofeng Wang, Haiyun Liu, Dongwon Kim, Ang Li, Sam S Lee, Andrew M Overmiller, Yingchao Xue, Sashank Reddy, Nathan K Archer, Lloyd S Miller, Jianshi Yu, Weiliang Huang, Jace W Jones, Sooah Kim, Maureen A Kane, Robert H Silverman, Luis A Garza","doi":"10.1172/JCI172595","DOIUrl":"10.1172/JCI172595","url":null,"abstract":"Mammalian injury responses are predominantly characterized by fibrosis and scarring rather than functional regeneration. This limited regenerative capacity in mammals could reflect a loss of proregeneration programs or active suppression by genes functioning akin to tumor suppressors. To uncover programs governing regeneration in mammals, we screened transcripts in human participants following laser rejuvenation treatment and compared them with mice with enhanced wound-induced hair neogenesis (WIHN), a rare example of mammalian organogenesis. We found that Rnasel-/- mice exhibit an increased regenerative capacity, with elevated WIHN through enhanced IL-36α. Consistent with RNase L's known role to stimulate caspase-1, we found that pharmacologic inhibition of caspases promoted regeneration in an IL-36-dependent manner in multiple epithelial tissues. We identified a negative feedback loop, where RNase L-activated caspase-1 restrains the proregenerative dsRNA-TLR3 signaling cascade through the cleavage of toll-like adaptor protein TRIF. Through integrated single-cell RNA-seq and spatial transcriptomic profiling, we confirmed OAS & IL-36 genes to be highly expressed at the site of wounding and elevated in Rnasel-/- mouse wounds. This work suggests that RNase L functions as a regeneration repressor gene, in a functional trade off that tempers immune hyperactivation during viral infection at the cost of inhibiting regeneration.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau. 睡眠-觉醒时体温的变化可调节 tau 的分泌，并与脑脊液和血浆 tau 相关。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-04 DOI: 10.1172/JCI182931

Geoffrey Canet, Felipe Da Gama Monteiro, Emma Rocaboy, Sofia Diego-Diaz, Boutheyna Khelaifia, Kelly Godbout, Aymane Lachhab, Jessica Kim, Daphne I Valencia, Audrey Yin, Hau-Tieng Wu, Jordan C Howell, Emily Blank, Francis Laliberté, Nadia Fortin, Emmanuelle Boscher, Parissa Fereydouni-Forouzandeh, Stéphanie Champagne, Isabelle Guisle, Sébastien S Hébert, Vincent Pernet, Haiyan Liu, William Lu, Ludovic Debure, David M Rapoport, Indu Ayappa, Andrew W Varga, Ankit Parekh, Ricardo S Osorio, Steve Lacroix, Mark P Burns, Brendan P Lucey, Esther M Blessing, Emmanuel Planel

{"title":"Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau.","authors":"Geoffrey Canet, Felipe Da Gama Monteiro, Emma Rocaboy, Sofia Diego-Diaz, Boutheyna Khelaifia, Kelly Godbout, Aymane Lachhab, Jessica Kim, Daphne I Valencia, Audrey Yin, Hau-Tieng Wu, Jordan C Howell, Emily Blank, Francis Laliberté, Nadia Fortin, Emmanuelle Boscher, Parissa Fereydouni-Forouzandeh, Stéphanie Champagne, Isabelle Guisle, Sébastien S Hébert, Vincent Pernet, Haiyan Liu, William Lu, Ludovic Debure, David M Rapoport, Indu Ayappa, Andrew W Varga, Ankit Parekh, Ricardo S Osorio, Steve Lacroix, Mark P Burns, Brendan P Lucey, Esther M Blessing, Emmanuel Planel","doi":"10.1172/JCI182931","DOIUrl":"10.1172/JCI182931","url":null,"abstract":"Sleep disturbance is bidirectionally associated with increased risks of Alzheimer's disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial given evidence indicates that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combine in vitro, in vivo and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, higher BT during wakefulness and sleep-deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway-I (UPS-I) components, including (i) intracellular tau dephosphorylation, (ii) caspase-3-mediated cleavage of tau (TauC3) and (iii) its membrane translocation through binding to PIP2 and syndecan-3. In humans, the increase in CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration, and the preventative potential of thermal interventions.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-04 DOI: 10.1172/JCI179137

Tanvi Potluri, Tianming You, Ping Yin, John Coon, Jonah J Stulberg, Yang Dai, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun

{"title":"Estrogen receptor-α ablation reverses muscle fibrosis and inguinal hernias.","authors":"Tanvi Potluri, Tianming You, Ping Yin, John Coon, Jonah J Stulberg, Yang Dai, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun","doi":"10.1172/JCI179137","DOIUrl":"10.1172/JCI179137","url":null,"abstract":"Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment that affects a noteworthy 50% of men by age 75 and necessitates surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Using a humanized mouse model that replicates the elevated skeletal muscle tissue estrogen concentrations seen in aging men, we identified estrogen receptor-α (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomics analyses of in vitro LAM fibroblasts from humanized mice unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and present non-surgical avenues for addressing inguinal hernias.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ZDHHC18 promotes renal fibrosis development by regulating HRAS palmitoylation.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-04 DOI: 10.1172/JCI180242

Di Lu, Gulibositan Aji, Guanyu Li, Yue Li, Wenlin Fang, Shuai Zhang, Ruiqi Yu, Sheng Jiang, Xia Gao, Yuhang Jiang, Qi Wang

{"title":"ZDHHC18 promotes renal fibrosis development by regulating HRAS palmitoylation.","authors":"Di Lu, Gulibositan Aji, Guanyu Li, Yue Li, Wenlin Fang, Shuai Zhang, Ruiqi Yu, Sheng Jiang, Xia Gao, Yuhang Jiang, Qi Wang","doi":"10.1172/JCI180242","DOIUrl":"10.1172/JCI180242","url":null,"abstract":"Fibrosis is the final common pathway leading to end-stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and the underlying mechanisms remain unclear. In this study, we observed that expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid-induced (FA-induced) renal fibrosis mouse models and was significantly upregulated in fibrotic kidneys of patients with CKD. Functionally, tubule-specific deletion of ZDHHC18 attenuated tubular epithelial cells' partial epithelial-mesenchymal transition (EMT) and then reduced the production of profibrotic cytokines and alleviated tubulointerstitial fibrosis. In contrast, ZDHHC18 overexpression exacerbated progressive renal fibrosis. Mechanistically, ZDHHC18 catalyzed the palmitoylation of HRAS, which was pivotal for its translocation to the plasma membrane and subsequent activation. HRAS palmitoylation promoted downstream phosphorylation of MEK/ERK and further activated Ras-responsive element-binding protein 1 (RREB1), enhancing SMAD binding to the Snai1 cis-regulatory regions. Taken together, our findings suggest that ZDHHC18 plays a crucial role in renal fibrogenesis and represents a potential therapeutic target for combating kidney fibrosis.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-04 DOI: 10.1172/JCI185149

Fang Yu, Shikan Zheng, Chunjie Yu, Sanhui Gao, Zuqi Shen, Rukiye Nar, Zhexin Liu, Shuang Huang, Lizi Wu, Tongjun Gu, Zhijian Qian

{"title":"KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer.","authors":"Fang Yu, Shikan Zheng, Chunjie Yu, Sanhui Gao, Zuqi Shen, Rukiye Nar, Zhexin Liu, Shuang Huang, Lizi Wu, Tongjun Gu, Zhijian Qian","doi":"10.1172/JCI185149","DOIUrl":"10.1172/JCI185149","url":null,"abstract":"Constitutively active mutations of KRAS are prevalent in non-small cell lung cancer (NSCLC). However, the relationship between these mutations and resistance to platinum-based chemotherapy and the underlying mechanisms remain elusive. In this study, we demonstrate that KRAS mutants confer resistance to platinum in NSCLC. Mechanistically, KRAS mutants mediate platinum resistance in NSCLC cells by activating ERK/JNK signaling, which inhibits AlkB homolog 5 (ALKBH5) N6-methyladenosine (m6A) demethylase activity by regulating posttranslational modifications (PTMs) of ALKBH5. Consequently, the KRAS mutant leads to a global increase in m6A methylation of mRNAs, particularly damage-specific DNA-binding protein 2 (DDB2) and XPC, which are essential for nucleotide excision repair. This methylation stabilized the mRNA of these 2 genes, thus enhancing NSCLC cells' capability to repair platinum-induced DNA damage and avoid apoptosis, thereby contributing to drug resistance. Furthermore, blocking KRAS-mutant-induced m6A methylation, either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by inhibiting methyltransferase-like 3 (METTL3) pharmacologically, significantly sensitizes KRAS-mutant NSCLC cells to platinum drugs in vitro and in vivo. Collectively, our study uncovers a mechanism that mediates KRAS-mutant-induced chemoresistance in NSCLC cells by activating DNA repair through the modulation of the ERK/JNK/ALKBH5 PTM-induced m6A modification in DNA damage repair-related genes.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

5-HT orchestrates Histone Serotonylation and Citrullination to Drive Neutrophil Extracellular Traps and Liver Metastasis.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-04 DOI: 10.1172/JCI183544

Kaiyuan Liu, Yingchao Zhang, Genyu Du, Xinyu Chen, Lingling Xiao, Luyao Jiang, Na Jing, Penghui Xu, Chaoxian Zhao, Yiyun Liu, Huifang Zhao, Yujiao Sun, Jinming Wang, Chaping Cheng, Deng Wang, Jiahua Pan, Wei Xue, Pengcheng Zhang, Zhi-Gang Zhang, Wei-Qiang Gao, Shu-Heng Jiang, Kai Zhang, Helen He Zhu

{"title":"5-HT orchestrates Histone Serotonylation and Citrullination to Drive Neutrophil Extracellular Traps and Liver Metastasis.","authors":"Kaiyuan Liu, Yingchao Zhang, Genyu Du, Xinyu Chen, Lingling Xiao, Luyao Jiang, Na Jing, Penghui Xu, Chaoxian Zhao, Yiyun Liu, Huifang Zhao, Yujiao Sun, Jinming Wang, Chaping Cheng, Deng Wang, Jiahua Pan, Wei Xue, Pengcheng Zhang, Zhi-Gang Zhang, Wei-Qiang Gao, Shu-Heng Jiang, Kai Zhang, Helen He Zhu","doi":"10.1172/JCI183544","DOIUrl":"https://doi.org/10.1172/JCI183544","url":null,"abstract":"Serotonin (5-HT) is a neurotransmitter that has been linked to tumorigenesis. Whether and how 5-HT modulates cells in the microenvironment to regulate tumor metastasis remains to be largely unknown. Here, we demonstrate that 5-HT is secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce neutrophil extracellular traps (NETs) in the liver, which in turn facilitates the recruitment of disseminated cancer cells and promotes liver metastasis. 5-HT induces histone serotonylation (H3Q5ser) and orchestrates histone citrullination (H3cit) in neutrophils to trigger chromatin decondensation and facilitate the formation of NETs. Interestingly, we uncover in this process a reciprocally reinforcing effect between H3Q5ser and H3cit and a crosstalk between the respective writers TGM2 and PAD4. Genetic ablation or pharmacological targeting of TGM2, or inhibiting 5-HT transporter (SERT) with the FDA-approved antidepressant drug fluoxetine reduces H3Q5ser and H3cit modifications, suppresses NETs formation, and effectively inhibits NEPC, small cell lung cancer, and thyroid medullary cancer liver metastasis. Collectively, the 5-HT-triggered NETs production highlights a new targetable neurotransmitter-immune axis in driving liver metastasis of neuroendocrine cancers.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A deafness-blindness syndrome results from ATF6-based disruption of the unfolded protein response.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-03 DOI: 10.1172/JCI188708

Yuvraj Joshi, Jeffrey N Savas

引用次数: 0

HMGA1 is a crucial mediator of colon tumorigenesis driven by the loss of APC.

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-03 DOI: 10.1172/JCI187442

Yuxiang Wang, Mikayla Ybarra, Zhenghe Wang

引用次数: 0

Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells. 核梭杆菌通过肿瘤干细胞的新生促进结直肠癌。

IF 13.3 1区医学

Journal of Clinical Investigation Pub Date : 2025-02-03 DOI: 10.1172/JCI181595

Qinying Wang, Tingting Hu, Qinyuan Zhang, Yichi Zhang, Xiaoxu Dong, Yutao Jin, Jinming Li, Yangyang Guo, Fanying Guo, Ziying Chen, Peijie Zhong, Yongzhi Yang, Yanlei Ma

{"title":"Fusobacterium nucleatum promotes colorectal cancer through neogenesis of tumor stem cells.","authors":"Qinying Wang, Tingting Hu, Qinyuan Zhang, Yichi Zhang, Xiaoxu Dong, Yutao Jin, Jinming Li, Yangyang Guo, Fanying Guo, Ziying Chen, Peijie Zhong, Yongzhi Yang, Yanlei Ma","doi":"10.1172/JCI181595","DOIUrl":"10.1172/JCI181595","url":null,"abstract":"Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both patients with CRC and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated lymphocyte antigen 6 complex, locus A+ ( LY6A+, also known as stem cell antigen 1 [Sca-1]) revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a glycosylphosphatidylinositol-anchored (GPI-anchored) membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced the upregulation of ribosomal protein S14 (RPS14) via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, analysis of clinical CRC cohorts revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum/LY6A/RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0