Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function

Benjamin J. Jenkins, Yasmin R. Jenkins, Fernando M. Ponce-Garcia, Chloe Moscrop, Iain A. Perry, Matthew D. Hitchings, Alejandro H. Uribe, Federico Bernuzzi, Simon Eastham, James G. Cronin, Ardena Berisha, Alexandra Howell, Joanne Davies, Julianna Blagih, Marta Williams, Morgan Marsden, Douglas J. Veale, Luke C. Davies, Micah Niphakis, David K. Finlay, Linda V. Sinclair, Benjamin F. Cravatt, Andrew E. Hogan, James A. Nathan, Ian R. Humphreys, Ursula Fearon, David Sumpton, Johan Vande Voorde, Goncalo Dias do Vale, Jeffrey G. McDonald, Gareth W. Jones, James A. Pearson, Emma E. Vincent and Nicholas Jones ()
Additional contact information
Benjamin J. Jenkins: Swansea University
Yasmin R. Jenkins: Swansea University
Fernando M. Ponce-Garcia: Swansea University
Chloe Moscrop: Biomedical Sciences Building
Iain A. Perry: Swansea University
Matthew D. Hitchings: Swansea University
Alejandro H. Uribe: Switchback Road
Federico Bernuzzi: Switchback Road
Simon Eastham: Biomedical Sciences Building
James G. Cronin: Swansea University
Ardena Berisha: Co
Alexandra Howell: Cardiff University
Joanne Davies: Cardiff University
Julianna Blagih: 1 Midland Road
Marta Williams: Cardiff University
Morgan Marsden: Cardiff University
Douglas J. Veale: St Vincent’s University Hospital
Luke C. Davies: Swansea University
Micah Niphakis: Department of Chemistry, Scripps Research
David K. Finlay: Trinity College Dublin
Linda V. Sinclair: University of Dundee
Benjamin F. Cravatt: Department of Chemistry, Scripps Research
Andrew E. Hogan: Co
James A. Nathan: University of Cambridge
Ian R. Humphreys: Cardiff University
Ursula Fearon: Trinity College Dublin
David Sumpton: Switchback Road
Johan Vande Voorde: Switchback Road
Goncalo Dias do Vale: University of Texas Southwestern Medical Center
Jeffrey G. McDonald: University of Texas Southwestern Medical Center
Gareth W. Jones: Biomedical Sciences Building
James A. Pearson: Cardiff University
Emma E. Vincent: University of Bristol
Nicholas Jones: Swansea University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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 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 murine models 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 in female mice. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T-cell-mediated inflammation.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-65417-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65417-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-65417-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().