TY - JOUR
T1 - Mitochondrial ABHD11 inhibition drives sterol metabolism to modulate T-cell effector function
AU - Jenkins, Benjamin J.
AU - Jenkins, Yasmin R.
AU - Ponce-Garcia, Fernando M.
AU - Moscrop, Chloe
AU - Perry, Iain A.
AU - Hitchings, Matthew D.
AU - Uribe, Alejandro H.
AU - Bernuzzi, Federico
AU - Eastham, Simon
AU - Cronin, James G.
AU - Berisha, Ardena
AU - Howell, Alexandra
AU - Davies, Joanne
AU - Blagih, Julianna
AU - Williams, Marta
AU - Marsden, Morgan
AU - Veale, Douglas J.
AU - Davies, Luke C.
AU - Niphakis, Micah
AU - Finlay, David K.
AU - Sinclair, Linda V.
AU - Cravatt, Benjamin F.
AU - Hogan, Andrew E.
AU - Nathan, James A.
AU - Humphreys, Ian R.
AU - Fearon, Ursula
AU - Sumpton, David
AU - Vande Voorde, Johan
AU - Vale, Goncalo Dias do
AU - McDonald, Jeffrey G.
AU - Jones, Gareth W.
AU - Pearson, James A.
AU - Vincent, Emma E.
AU - Jones, Nicholas
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/11/3
Y1 - 2025/11/3
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-025-65417-4
DO - 10.1038/s41467-025-65417-4
M3 - Article (Academic Journal)
SN - 2041-1723
VL - 16
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 9484
ER -
