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

## TL;DR

Inhibiting a mitochondrial protein called ABHD11 reduces inflammation in T-cells by altering cholesterol metabolism, offering a potential new treatment for autoimmune diseases.

## Contribution

This study reveals that ABHD11 inhibition modulates T-cell function through 24,25-epoxycholesterol and liver X receptor activation, suggesting its potential as a drug target for autoimmune conditions.

## Key findings

- Pharmacological inhibition of ABHD11 reduces cytokine production in human and mouse T-cells.
- ABHD11 inhibition increases 24,25-epoxycholesterol biosynthesis and activates liver X receptors.
- Targeting ABHD11 delays diabetes onset in a mouse model of type 1 diabetes.

## 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.

α/β-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase, and its expression in CD4 + T-cells has been linked to remission status in rheumatoid arthritis. Here the authors report that pharmacological inhibition of ABHD11 modulates T-cell effector function via increased 24,25-epoxycholesterol biosynthesis and subsequent liver X receptor activation.