{"title":"鹅去氧胆酸通过FXR/Myc/ p -选择素轴调节肝内皮细胞的淤胆生态位","authors":"Peng Zhang, Xinying Li, Jinyuan Liang, Yuanwen Zheng, Yao Tong, Jing Shen, Yatai Chen, Penghu Han, Shuzheng Chu, Ruirui Liu, Mengqi Zheng, Yunjiao Zhai, Xiaolong Tang, Cuijuan Zhang, Hui Qu, Ping Mi, Jin Chai, Detian Yuan, Shiyang Li","doi":"10.1038/s41467-025-57351-2","DOIUrl":null,"url":null,"abstract":"<p>Cholestatic liver diseases are characterized by excessive bile acid accumulation in the liver. Endothelial cells (ECs) shape the local microenvironment in both normal conditions and liver injury, yet their role in cholestasis is unclear. Through a comparative analysis of single-cell RNA sequencing data from various murine models of liver injury, we identify distinctive Myc activation within ECs during obstructive cholestasis resulting from bile duct ligation (BDL). Myc overexpression in ECs significantly upregulates P-selectin, increasing neutrophil infiltration and worsening cholestatic liver injury. This process occurs through the FXR, activated by chenodeoxycholic acid (CDCA) and its conjugate TCDCA. Inhibiting P-selectin with PSI-697 reduces neutrophil recruitment and alleviates injury. Cholestatic patient liver samples also show elevated Myc and P-selectin in ECs, along with increased neutrophils. The findings identify ECs as key drivers of cholestatic liver injury through a Myc-driven program and suggest that targeting the CDCA/FXR/Myc/P-selectin axis may offer a therapeutic approach.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"279 1","pages":""},"PeriodicalIF":15.7000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chenodeoxycholic acid modulates cholestatic niche through FXR/Myc/P-selectin axis in liver endothelial cells\",\"authors\":\"Peng Zhang, Xinying Li, Jinyuan Liang, Yuanwen Zheng, Yao Tong, Jing Shen, Yatai Chen, Penghu Han, Shuzheng Chu, Ruirui Liu, Mengqi Zheng, Yunjiao Zhai, Xiaolong Tang, Cuijuan Zhang, Hui Qu, Ping Mi, Jin Chai, Detian Yuan, Shiyang Li\",\"doi\":\"10.1038/s41467-025-57351-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Cholestatic liver diseases are characterized by excessive bile acid accumulation in the liver. Endothelial cells (ECs) shape the local microenvironment in both normal conditions and liver injury, yet their role in cholestasis is unclear. Through a comparative analysis of single-cell RNA sequencing data from various murine models of liver injury, we identify distinctive Myc activation within ECs during obstructive cholestasis resulting from bile duct ligation (BDL). Myc overexpression in ECs significantly upregulates P-selectin, increasing neutrophil infiltration and worsening cholestatic liver injury. This process occurs through the FXR, activated by chenodeoxycholic acid (CDCA) and its conjugate TCDCA. Inhibiting P-selectin with PSI-697 reduces neutrophil recruitment and alleviates injury. Cholestatic patient liver samples also show elevated Myc and P-selectin in ECs, along with increased neutrophils. The findings identify ECs as key drivers of cholestatic liver injury through a Myc-driven program and suggest that targeting the CDCA/FXR/Myc/P-selectin axis may offer a therapeutic approach.</p>\",\"PeriodicalId\":19066,\"journal\":{\"name\":\"Nature Communications\",\"volume\":\"279 1\",\"pages\":\"\"},\"PeriodicalIF\":15.7000,\"publicationDate\":\"2025-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Communications\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1038/s41467-025-57351-2\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-57351-2","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
摘要
胆汁淤积性肝病的特点是肝脏中胆汁酸积聚过多。内皮细胞（ECs）在正常情况和肝损伤情况下塑造局部微环境，但它们在胆汁淤积中的作用尚不清楚。通过对来自不同小鼠肝损伤模型的单细胞RNA测序数据的比较分析，我们发现在胆管结扎（BDL）导致的阻塞性胆汁淤滞期间，ECs内Myc的独特激活。Myc在ECs中的过表达可显著上调p -选择素，增加中性粒细胞浸润，加重胆汁淤积性肝损伤。这个过程通过FXR发生，由鹅去氧胆酸（CDCA）及其偶联物TCDCA激活。PSI-697抑制p -选择素可减少中性粒细胞募集，减轻损伤。胆汁淤积症患者的肝脏样本也显示ec中Myc和p -选择素升高，同时中性粒细胞增加。研究结果表明，通过Myc驱动程序，ECs是胆汁淤积性肝损伤的关键驱动因素，并表明靶向CDCA/FXR/Myc/ p -选择素轴可能提供一种治疗方法。
Chenodeoxycholic acid modulates cholestatic niche through FXR/Myc/P-selectin axis in liver endothelial cells
Cholestatic liver diseases are characterized by excessive bile acid accumulation in the liver. Endothelial cells (ECs) shape the local microenvironment in both normal conditions and liver injury, yet their role in cholestasis is unclear. Through a comparative analysis of single-cell RNA sequencing data from various murine models of liver injury, we identify distinctive Myc activation within ECs during obstructive cholestasis resulting from bile duct ligation (BDL). Myc overexpression in ECs significantly upregulates P-selectin, increasing neutrophil infiltration and worsening cholestatic liver injury. This process occurs through the FXR, activated by chenodeoxycholic acid (CDCA) and its conjugate TCDCA. Inhibiting P-selectin with PSI-697 reduces neutrophil recruitment and alleviates injury. Cholestatic patient liver samples also show elevated Myc and P-selectin in ECs, along with increased neutrophils. The findings identify ECs as key drivers of cholestatic liver injury through a Myc-driven program and suggest that targeting the CDCA/FXR/Myc/P-selectin axis may offer a therapeutic approach.
期刊介绍：
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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