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
- Nicholas Jones
2025-11-03
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.