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journal article·2026-02Open access

FSTL1 Orchestrates Metabolic‐Epigenetic Crosstalk: Glycolysis‐Dependent H3K18 Lactylation Drives Cartilage Fibrosis in Osteoarthritis

Feng Lu, Yunyuan Yu, Guangrong Yin, Huiqun Hu, Shishuo Li, Yuting Tang, Yimin Liu, Maoyuan Li, Liang liang Wang, Chao Xu, Gongyin Zhao, Baojun Zhou, Yuji Wang

Advanced Science· Volume 13· Issue 8
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Source abstract

Abstract

Abstract 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.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Osteoarthritis Treatment and Mechanisms · Mesenchymal stem cell research · Total Knee Arthroplasty Outcomes

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Orthopedics The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital) Changzhou Jiangsu 213003 P. R. China

Nanjing Medical University Nanjing 210000 P. R. China

Articular Orthopaedics The Third Affiliated Hospital of Soochow University Changzhou 213003 P. R. China

Department of Thoracic Radiation Oncology Zhejiang Cancer Hospital Hangzhou 310022 P. R. China

Department of Infectious Diseases the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310009 P. R. China

Graduate School of Dalian Medical University Dalian Liaoning 116044 P. R. China

Department of Medical Genetics Nanjing Medical University Longmian Road 101 Nanjing 211166 P. R. China

Jiangsu Key Laboratory of Xenotransplantation Nanjing Medical University Longmian Road 101 Nanjing 211166 P. R. China

Department of Orthopedics The Third Affiliated Hospital of Gansu University of Chinese Medicine 222 Silong Road Baiyin 730900 P. R. China

Center for bone disease rehabilitation The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital) Changzhou Jiangsu 213003 P. R. China

Department of Orthopedic Surgery and Biochemistry and Molecular Biology Mayo Clinic Rochester MN 55905 USA

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