Lactate programs CRIP1 protein lactylation to drive synovial proliferation in rheumatoid arthritis

  • JCI Insight. 2026 Jun 8;11(11):e200928. doi: 10.1172/jci.insight.200928.
Meican Ma  1 ,  Yu Zhou  2 ,  Qianlin Li  1 ,  Zhao Wang  1 ,  Shangqi Guan  3 ,  Xiaoxue Wang  4 ,  Han Zhao  5 ,  Zhenke Wen  6  7 ,  Ting Liu  1 ,  Fenghong Yuan  1
Affiliations
  • 1. Department of Rheumatology and Immunology and.
  • 2. Department of Clinical Research Center, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 3. Department of Rheumatology and Immunology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, Shenzhen, Guangdong, China.
  • 4. Department of Rheumatology and Immunology, The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, Heilongjiang, China.
  • 5. Department of Endocrinology and Metabolism, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 6. The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, Jiangsu, China.
  • 7. Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Biomedical Basic Research Center of Jiangsu Province, Soochow University, Suzhou, Jiangsu, China.
PMID: 42258744 DOI: 10.1172/jci.insight.200928
Abstract

Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA), yet its mechanism remains unclear. RA synovium exhibits metabolic shift, characterized by upregulated glycolysis and enhanced lactate production. In this study, we elucidated the mechanism underlying the roles of lactate metabolism and protein lactylation in RA pathology. In patients with RA, both lactate production and protein lactylation were elevated and showed a positive correlation with clinical disease activity. These changes were further implicated in driving synovial proliferation. Among the lactylated proteins, Cysteine-rich intestinal protein 1 (CRIP1) exhibited a marked increase in modification and played a central role in promoting synovial proliferation. Mechanistically, CRIP1 underwent MOF-mediated lactylation in RA synovial fibroblasts. Lactylated CRIP1 hijacked the cell-cycle regulator p21, disrupting its interaction with cyclin-dependent kinase 2 (CDK2), thereby facilitating the G1/S phase transition. Functionally, AAV-mediated delivery of a lactylation-deficient CRIP1 K49R significantly reduced synovial proliferation compared with WT CRIP1. Peptide-based interventions targeting CRIP1 K49 lactylation effectively inhibited synovial hyperplasia and disease severity in both Collagen II-induced arthritis (CIA) and humanized NSG chimeric models. Collectively, CRIP1 protein lactylation drives synovial proliferation in RA by hijacking p21 from CDK2, thereby facilitating cell cycle progression. Targeting this pathway may serve as a promising strategy for RA.

Keywords
Autoimmunity; Metabolism; Rheumatology.
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