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

Jenkins, Benjamin J., Jenkins, Yasmin R., Ponce-Garcia, Fernando M., Moscrop, Chloe, Perry, Iain A., Hitchings, Matthew D., Uribe, Alejandro H., Bernuzzi, Federico, Eastham, Simon, Cronin, James G., Berisha, Ardena, Howell, Alexandra, Davies, Joanne, Blagih, Julianna, Williams, Marta, Marsden, Morgan, Veale, Douglas J., Davies, Luke C., Niphakis, Micah, Finlay, David K., Sinclair, Linda V., Cravatt, Benjamin F., Hogan, Andrew E., Nathan, James A., Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337, Fearon, Ursula, Sumpton, David, Vande Voorde, Johan, Vale, Goncalo Dias do, McDonald, Jeffrey G., Jones, Gareth W., Pearson, James A. ORCID: https://orcid.org/0000-0002-2867-2269, Vincent, Emma E. and Jones, Nicholas 2025. Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function. Nature Communications 16 (1) , 9484. 10.1038/s41467-025-65417-4

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	12 November 2025
Date of Acceptance:	13 October 2025
Last Modified:	12 Nov 2025 12:00
URI:	https://orca.cardiff.ac.uk/id/eprint/182364

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