2025-11-03 スウォンジー大学
<関連情報>
- https://www.swansea.ac.uk/press-office/news-events/news/2025/11/new-research-uncovers-promising-target-for-autoimmune-disease-treatment.php
- https://www.nature.com/articles/s41467-025-65417-4
ミトコンドリアABHD11阻害はステロール代謝を促進し、T細胞エフェクター機能を調節する 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,… Nicholas Jones
Nature Communications Published:03 November 2025
DOI:https://doi.org/10.1038/s41467-025-65417-4
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.
