Palmitoyl-protein thioesterase-1 in health and disease.

The palmitoylation/depalmitoylation cycle regulates protein localization, function, and stability, playing essential roles in signal transduction, membrane trafficking, and neuronal activity. Understanding the enzymes involved may reveal novel therapeutic targets. Palmitoyl-protein thioesterase-1 (PPT1) is a key depalmitoylase that removes palmitate from target proteins. Deficiency in PPT1 causes Batten disease (CLN1), a fatal neurodegenerative disorder, while overexpression has been linked to various cancers. Emerging evidence also implicates PPT1 in other neurodegenerative, autoimmune, and reproductive diseases. Recognizing its broad biological significance, PPT1 is an enzyme with growing therapeutic interest; however, translational hurdles still remain. This review provides an overview of PPT1 structure, enzymatic activity, substrates, and roles across systems, alongside a landscape of PPT1-targeted drugs in preclinical and clinical development that will inform future research.