文献类型：期刊文献

英文题名：USP20-Driven Cholesterol Metabolism Links Inflammatory Signaling to Malignancy and Stromal Coevolution in Pancreatic Cancer

作者：Jiang, Xiangyan[1,2,3];Zhao, Bin[1,2,3];Wang, Tao[1,2,4];Ma, Yong[1,2,4];Liu, Wenbo[1,2];Sun, Haonan[1,2];Li, Zhigang[5];Wang, Keshen[1,2];He, Qichen[1,2];Guan, Xiaoying[6];Qin, Long[3,4,7];Shi, Wengui[3,4,7];Dong, Yuman[3,4,7];Ye, Zhenzhen[8];Zhou, Chengliang[9];He, Xiaoe[1,2];Qing, Huiguo[1];Long, Bo[1,2];Zhou, Huinian[1,2];Yu, Zeyuan[2,4];Jiao, Zuoyi[2,3,4,10]

第一作者：Jiang, Xiangyan

通信作者：Jiao, ZY[1]

机构：[1]Lanzhou Univ, Clin Med Sch 2, Lanzhou, Peoples R China;[2]Lanzhou Univ Second Hosp, Dept Gen Surg, Lanzhou 730000, Peoples R China;[3]Lanzhou Univ, Gansu Tumor Immunol Basic Disciplines Res Ctr, Lanzhou, Gansu, Peoples R China;[4]Lanzhou Univ Second Hosp, Gansu Prov High Altitude High Incidence Canc Bioba, Lanzhou, Peoples R China;[5]Gansu Prov Canc Hosp, Dept Head & Neck Surg, Lanzhou, Peoples R China;[6]Lanzhou Univ Second Hosp, Dept Pathol, Lanzhou, Peoples R China;[7]Lanzhou Univ Second Hosp, Cuiying Biomed Res Ctr, Lanzhou, Peoples R China;[8]Gansu Univ Chinese Med, Sch Clin Med 1, Lanzhou, Peoples R China;[9]Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Nijmegen, Netherlands;[10]Lanzhou Univ Second Hosp, Gansu Prov Ind Technol Ctr Canc Immunotherapy, Lanzhou, Peoples R China

第一机构：Lanzhou Univ, Clin Med Sch 2, Lanzhou, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ Second Hosp, Dept Gen Surg, Lanzhou 730000, Peoples R China.

年份：2026

卷号：86

期号：3

起止页码：712

外文期刊名：CANCER RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001677471500012)】；

基金：This work was supported by National Natural Science Foundation of China (grant numbers 82160487 to Z. Yu, 823B2073 to X. Jiang, 824B2080 to Y. Ma, 82473377 to Z. Jiao, and 8246110030 to H. Zhou), Natural Science Foundation of Gansu Province (24JRRA381 to X. Jiang), and Foundation for Innovation Groups of Basic Research in Gansu Province (25JRRA800 to Z. Jiao).

语种：英文

摘要：Inflammatory signaling, metabolic reprogramming, and stromal complexity have emerged as core hallmarks of pancreatic ductal adenocarcinoma (PDAC). Cross-talk between these programs could represent potential targets to concurrently perturb multiple tumor-promoting processes. By integrating multiomics data from clinical cohorts, patient-derived organoids, and autochthonous models, we uncovered tumor-intrinsic inflammatory cascades in PDAC as master regulators of mevalonate pathway hijacking, which drove both malignant progression and stromal coevolution. TNFSF13B+ tumor-associated macrophages activated STAT3 signaling in neoplastic epithelia, leading to the transcriptional upregulation of USP20. This deubiquitinase stabilized HMGCR to potentiate mevalonate flux, resulting in cholesterol and geranylgeranyl pyrophosphate overproduction. Stimulation of YAP/TAZ signaling induced by the USP20-mediated metabolic alterations promoted tumor cell proliferation and triggered the activation of cancer-associated fibroblasts. Genetic ablation or pharmacologic inhibition of USP20 using a selective inhibitor reversed tumor metabolic dysregulation, suppressing both tumor growth and stromal desmoplasia. Furthermore, the combination of USP20 inhibition and anti-PD-1/anti-CTLA4 immunotherapy resulted in enhanced antitumor efficacy. These findings reveal the STAT3-USP20-HMGCR axis as a central coordinator of PDAC malignancy and position USP20 inhibition as a strategy to suppress oncogenic signaling, perturb metabolic reprogramming, and reverse microenvironmental remodeling.Significance: Targeting USP20 disrupts coevolution of pancreatic ductal adenocarcinoma and the tumor microenvironment and enhances immune checkpoint inhibitor efficacy by blocking mevalonate metabolism rewiring, providing a dual-action therapeutic approach for pancreatic cancer.