# A Lipidomic Approach to Studying the Downregulation of Free Fatty Acids by Cytosolic Phospholipase A2 Inhibitors

## TL;DR

This study uses lipidomics to show how cytosolic phospholipase A2 inhibitors change free fatty acid levels in cells, which could impact diseases like cancer and neurodegeneration.

## Contribution

The study introduces a lipidomic approach to reveal distinct free fatty acid profiles after treatment with cytosolic phospholipase A2 inhibitors.

## Key findings

- GIVA cPLA2 inhibitors reduce not only arachidonic acid but also other fatty acids like linoleic and caproic acid.
- Different inhibitors produce unique intracellular free fatty acid profiles, indicating varied effects on fatty acid metabolism.
- Downregulation of fatty acids may influence metabolic reprogramming in neurodegenerative diseases and cancer.

## Abstract

Inhibitors of cytosolic phospholipase A2 (GIVA cPLA2) have received great attention, since this enzyme is involved in a number of inflammatory diseases, including cancer and auto-immune and neurodegenerative diseases. Traditionally, the effects of GIVA cPLA2 inhibitors in cells have been studied by determining the inhibition of arachidonic acid release. However, although to a lesser extent, GIVA cPLA2 may also hydrolyze glycerophospholipids, releasing other free fatty acids (FFAs), such as linoleic acid or oleic acid. In the present work, we applied a liquid chromatography–high-resolution mass spectrometry method to study the levels of intracellular FFAs, after treating cells with selected GIVA cPLA2 inhibitors. Six inhibitors belonging to different chemical classes were studied, using SH-SY5Y neuroblastoma cells as a model. This lipidomic approach revealed that treatment with each inhibitor created a distinct intracellular FFA profile, suggesting not only inhibitory potency against GIVA cPLA2, but also other parameters affecting the outcome. Potent inhibitors were found to reduce not only arachidonic acid, but also other long-chain FAs, such as adrenic or linoleic acid, even medium-chain FAs, such as caproic or caprylic acid, suggesting that GIVA cPLA2 inhibitors may affect FA metabolic pathways in general. The downregulation of intracellular FFAs may have implications in reprogramming FA metabolism in neurodegenerative diseases and cancer.