2. Academic Validation
  3. ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA

ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA

  • Cell Rep. 2025 Jun 24;44(6):115851. doi: 10.1016/j.celrep.2025.115851.
Huiyan Ji 1,  Wanwan Jiang 1,  Juan Zhang 2,  Mengdi Liu 1,  Danhua Su 1,  Jiaxin Lei 1,  Lingyi Li 1,  Ming Zheng 1,  Ting Liu 3,  Zhichun Liu 4,  Qinghua Cao 5,  Lin Xu 6,  Sidong Xiong 1,  Zhenke Wen 7
Affiliations

Affiliations

  • 1 The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, China.
  • 2 Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou, China.
  • 3 Department of Rheumatology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
  • 4 Department of Rheumatology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.
  • 5 Renal Medicine, Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, St Leonards, NSW, Australia; Royal North Shore Hospital, St Leonards, NSW, Australia.
  • 6 Department of Immunology, Zunyi Medical University, Zunyi, China.
  • 7 The Fourth Affiliated Hospital of Soochow University, Institutes of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Soochow University, Suzhou, China; Jiangsu Key Laboratory of Infection and Immunity, MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, China. Electronic address: zkwen@suda.edu.cn.
PMID: 40516055 DOI: 10.1016/j.celrep.2025.115851
Abstract

T cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), yet the underlying molecular mechanisms governing their fate remain elusive. Here, we identify cytosolic mitochondrial DNA (mtDNA) as an intrinsic trigger for driving effector T cell differentiation in patients with SLE. Specifically, accumulated cytosolic mtDNA is sensed by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which enhances the transcription of GLUT1 and glycolysis in SLE T cells. This metabolic shift reduces lipogenesis and depletes free fatty acids (FFAs), impairing the N-myristylation and lysosomal localization of AMP-activated protein kinase (AMPK). Inactive AMPK fails to restrain mammalian target of rapamycin complex 1 (mTORC1), leading to its hyperactivation and driving the mal-differentiation of effector T cells. Consequently, interventions targeting ENPP1, glycolysis, AMPK, and mTORC1 effectively inhibit the generation of immunoglobulin (Ig)G anti-double-stranded DNA (dsDNA) and the progression of lupus nephritis in humanized SLE chimeras. Overall, our findings uncover an mtDNA-ENPP1-metabolic axis that governs effector T cell fate in autoimmunity.

Keywords

AMPK; CP: Immunology; CP: Molecular biology; ENPP1; SLE; T cell; mitochondrial DNA.

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