This review explains that a reversible fatty tag called S‑acylation on brain proteins influences inflammation and neurodegenerative diseases, and that the enzymes adding (zDHHC) or removing (thioesterases) this tag could be drug targets, but no direct consumer‑level actions are described.

Neuroinflammation is a hallmark of many neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, and infantile neuronal ceroid lipofuscinosis. Dynamic protein S-acylation, a reversible lipid post-translational modification, is an important regulator in these processes. S-acylation is catalysed by the zDHHC palmitoyl acyltransferases, and removal of the acyl groups is mediated by acyl-protein thioesterases. S-acylation controls the localisation, stability, and function of around 48 % of all proteins in the nervous system, including synaptic scaffolds, ion channels, immune receptors, and trafficking proteins. Moreover, dysregulated S-acylation contributes to synaptic loss, aberrant immune signalling, and neurodegeneration. This review examines proteins implicated in neuroinflammation with reported S-acylase or deacylase activity, outlines current knowledge on disease-related alterations in S-acylation, and assesses the therapeutic promise of available small-molecule modulators. Linking the activity of these enzymes with human disease highlights the potential of reversible S-acylation as a source of innovative targets for drug discovery in neuroinflammation.