2. Academic Validation
  3. ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity

ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity

  • bioRxiv. 2025 Mar 19:2025.03.19.643996. doi: 10.1101/2025.03.19.643996.
Benjamin J Jenkins 1,  Yasmin R Jenkins 1,  Fernando M Ponce-Garcia 1,  Chloe Moscrop 2,  Iain A Perry 1,  Matthew D Hitchings 1,  Alejandro H Uribe 3,  Federico Bernuzzi 3,  Simon Eastham 2,  James G Cronin 1,  Ardena Berisha 4,  Alexandra Howell 5,  Joanne Davies 5,  Julianna Blagih 6 7,  Douglas J Veale 8,  Luke C Davies 1,  Micah Niphakis 9,  David K Finlay 10,  Linda V Sinclair 11,  Benjamin F Cravatt 9,  Andrew E Hogan 4,  James A Nathan 12,  Ursula Fearon 13,  David Sumpton 3,  Johan Vande Voorde 3 14,  Goncalo Dias do Vale 15,  Jeffrey G McDonald 15,  Gareth W Jones 2,  James A Pearson 5,  Emma E Vincent 16 17,  Nicholas Jones 1
Affiliations

Affiliations

  • 1 Institute of Life Science, Swansea University Medical School, Swansea University, SA2 8PP, UK.
  • 2 Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, BS8 1TD, UK.
  • 3 Cancer Research UK Scotland Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
  • 4 Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland.
  • 5 Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN, UK.
  • 6 The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 7 University of Montreal, Maisonneuve-Rosemont Hospital Research Centre, Montreal, 5414 Assomption Blvd, H1T 2M4, Canada.
  • 8 EULAR Centre of Excellence, Centre for Arthritis and Rheumatic Diseases, St Vincent's University Hospital, Dublin, Ireland.
  • 9 Department of Chemistry, Scripps Research, La Jolla, California 92037, United States.
  • 10 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland.
  • 11 Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • 12 Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, CB2 0AW, UK.
  • 13 Molecular Rheumatology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland.
  • 14 School of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, G61 1QH, UK.
  • 15 Center for Human Nutrition, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States.
  • 16 School of Translational Health Sciences, Dorothy Hodgkin Building, University of Bristol, Bristol, BS1 3NY, UK.
  • 17 Integrative Epidemiology Unit, School of Population Health Science, University of Bristol, Bristol, BS8 2BN, UK.
PMID: 40166327 DOI: 10.1101/2025.03.19.643996
Abstract

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of α-ketoglutarate dehydrogenase (α-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity.

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