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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-11-03
DOI
https://doi.org/10.1038/s41467-025-65417-4
Primary Topic
Cholesterol and Lipid Metabolism
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Micah J. Niphakis, Jeffrey G. McDonald, Gareth W. Jones, David Sumpton et al.
Nature Communications
Cholesterol and Lipid Metabolism
article

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

Micah J. Niphakis, Jeffrey G. McDonald, Gareth W. Jones, David Sumpton, Ursula Fearon, Joanne Davies, James A. Nathan, Fernando M. Ponce-Garcia, Douglas J. Veale, J. Cronin, Ian R. Humphreys, Ardena Berisha, Johan Vande Voorde, David K. Finlay, Federico Bernuzzi, Julianna Blagih, Iain Perry, Benjamin F. Cravatt, Simon Eastham, Morgan Marsden, Nicholas Jones, Marta Williams, Andrew E. Hogan, Alexandra Howell, Luke C. Davies, Yasmin R Jenkins, Chloe Moscrop, Gonçalo Vale, B. Jenkins, Emma E. Vincent, Linda V. Sinclair, Alejandro Huerta Uribe, James A. Pearson, Matthew D. Hitchings
article en

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.

Nature CommunicationsVol. 16(1)
Scripps Institution of Oceanography (US), National University of Ireland, Maynooth (IE), University of Dundee (GB), Trinity College Dublin (IE), University of Cambridge (GB), The Francis Crick Institute (GB), Cancer Research UK (GB), Hôpital Maisonneuve-Rosemont (CA), University of Bristol (GB), Swansea University (GB), St. Vincent's University Hospital (IE), Scripps (United States) (US), Cancer Research UK Scotland Institute (GB), Institute of Infection and Immunity (CA), University of Glasgow (GB), Cardiff University (GB), The University of Texas Southwestern Medical Center (US)
Cancer Research UK, Diabetes UK, University of Glasgow, Swansea University, Servier, Versus Arthritis, National Institutes of Health, Medical Research Council
Openalex Percentile: Top 50%
Cholesterol and Lipid Metabolism
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.