2. Academic Validation
  3. FSTL1 Orchestrates Metabolic-Epigenetic Crosstalk: Glycolysis-Dependent H3K18 Lactylation Drives Cartilage Fibrosis in Osteoarthritis

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

  • Adv Sci (Weinh). 2025 Nov 26:e12002. doi: 10.1002/advs.202512002.
Feng Lu 1 2,  Yunyuan Yu 3,  Guangrong Yin 1,  Huiqun Hu 4 5,  Shishuo Li 1 6,  Yuting Tang 7 8,  Yimin Liu 1 2,  Maoyuan Li 1 2,  Liang Liang Wang 1,  Chao Xu 1,  Gongyin Zhao 1,  Baojun Zhou 9,  Yuji Wang 1 9 10 11
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Third Affiliated Hospital of Nanjing Medical University (Changzhou No. 2 People's Hospital), Changzhou, Jiangsu, 213003, P. R. China.
  • 2 Nanjing Medical University, Nanjing, 210000, P. R. China.
  • 3 Articular Orthopaedics, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, P. R. China.
  • 4 Department of Thoracic Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, P. R. China.
  • 5 Department of Infectious Diseases, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, P. R. China.
  • 6 Graduate School of Dalian Medical University, Dalian, Liaoning, 116044, P. R. China.
  • 7 Department of Medical Genetics, Nanjing Medical University, Longmian Road 101, Nanjing, 211166, P. R. China.
  • 8 Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Longmian Road 101, Nanjing, 211166, P. R. China.
  • 9 Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Chinese Medicine, 222 Silong Road, Baiyin, 730900, P. R. China.
  • 10 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.
  • 11 Department of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA.
PMID: 41293926 DOI: 10.1002/advs.202512002
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.

Keywords

FSTL1; cartilage; fibrosis; glycolysis; lactylation; osteoarthrosis.

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