文献类型：期刊文献

英文题名：FSTL1 Orchestrates Metabolic-Epigenetic Crosstalk: Glycolysis-Dependent H3K18 Lactylation Drives Cartilage Fibrosis in Osteoarthritis

作者：Lu, Feng[1,2];Yu, Yunyuan[3];Yin, Guangrong[1];Hu, Huiqun[4,5];Li, Shishuo[1,6];Tang, Yuting[7,8];Liu, Yimin[1,2];Li, Maoyuan[1,2];Wang, Liang Liang[1];Xu, Chao[1];Zhao, Gongyin[1];Zhou, Baojun[9];Wang, Yuji[1,9,10,11]

第一作者：Lu, Feng

通信作者：Wang, YJ[1];Wang, YJ[2];Wang, YJ[3];Wang, YJ[4]

机构：[1]Nanjing Med Univ, Changzhou 2 Peoples Hosp, Dept Orthoped, Affiliated Hosp 3, Changzhou 213003, Jiangsu, Peoples R China;[2]Nanjing Med Univ, Nanjing 210000, Peoples R China;[3]Soochow Univ, Articular Orthopaed, Affiliated Hosp 3, Changzhou 213003, Peoples R China;[4]Zhejiang Canc Hosp, Dept Thorac Radiat Oncol, Hangzhou 310022, Peoples R China;[5]Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Infect Dis, Hangzhou 310009, Peoples R China;[6]Dalian Med Univ, Grad Sch, Dalian 116044, Liaoning, Peoples R China;[7]Nanjing Med Univ, Dept Med Genet, Longmian Rd 101, Nanjing 211166, Peoples R China;[8]Nanjing Med Univ, Jiangsu Key Lab Xenotransplantat, Longmian Rd 101, Nanjing 211166, Peoples R China;[9]Gansu Univ Chinese Med, Affiliated Hosp 3, Dept Orthoped, 222 Silong Rd, Baiyin 730900, Peoples R China;[10]Nanjing Med Univ, Changzhou 2 Peoples Hosp, Ctr Bone Dis Rehabil, Affiliated Hosp 3, Changzhou 213003, Jiangsu, Peoples R China;[11]Mayo Clin, Dept Orthoped Surg & Biochem & Mol Biol, Rochester, MN 55905 USA

第一机构：Nanjing Med Univ, Changzhou 2 Peoples Hosp, Dept Orthoped, Affiliated Hosp 3, Changzhou 213003, Jiangsu, Peoples R China

通信机构：[1]corresponding author), Nanjing Med Univ, Changzhou 2 Peoples Hosp, Dept Orthoped, Affiliated Hosp 3, Changzhou 213003, Jiangsu, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Affiliated Hosp 3, Dept Orthoped, 222 Silong Rd, Baiyin 730900, Peoples R China;[3]corresponding author), Nanjing Med Univ, Changzhou 2 Peoples Hosp, Ctr Bone Dis Rehabil, Affiliated Hosp 3, Changzhou 213003, Jiangsu, Peoples R China;[4]corresponding author), Mayo Clin, Dept Orthoped Surg & Biochem & Mol Biol, Rochester, MN 55905 USA.|[10735]甘肃中医药大学;

年份：2025

外文期刊名：ADVANCED SCIENCE

收录：;EI(收录号：20254919625634);Scopus(收录号：2-s2.0-105023328389);WOS:【SCI-EXPANDED(收录号:WOS:001623219100001)】；

基金：This study was supported by the Clinical Research Project of Changzhou Medical Center of Nanjing Medical University (CZKYCMCB202215). The authors want to thank all the patients who participated in the study. Thanks to Peizhen Wang from the University of Minnesota Twin Cities for his assistance.

语种：英文

外文关键词：cartilage; fibrosis; FSTL1; glycolysis; lactylation; osteoarthrosis

摘要：The progression of osteoarthritis (OA) is fundamentally characterized by the aberrant transformation of chondrocytes into a fibrotic phenotype, although the precise molecular mechanisms involved remain inadequately understood. In this study, the interplay between epigenetic modifications and metabolic reprogramming during the activation of fibrocartilage cells in osteoarthritis was investigated. The findings demonstrate that FSTL1 markedly upregulates key glycolytic enzymes, including LDHA, HK2, and PKM, in chondrocytes, triggering a "glycolytic burst" that results in elevated intracellular lactate levels. This accumulated lactate acts as a precursor for epigenetic modifications, specifically promoting the lactylation of histone H3 lysine 18 (H3K18la) in fibrocartilage cells, thereby facilitating the transcriptional activation of critical fibrosis-related genes such as Itga6, Cxcl10, and Parp16. Notably, pharmacological inhibition of the PI3K/mTOR pathway or lactate dehydrogenase significantly diminishes H3K18la levels and markers of chondrocyte fibrosis, while exogenous lactate supplementation can counteract this effect. In summary, this study unveils the core mechanism by which FSTL1 reshapes the epigenetic landscape of chondrocytes and drives the fibrotic process through the activation of the "glycolysis-lactate-H3K18la" cascade axis, offering a dual-target intervention strategy for OA involving metabolic reprogramming and epigenetic modification.