Palmitoylation-dependent modulation of CD36 trafficking and signaling integrates lipid uptake with metabolic disease pathogenesis.

CD36 is a multifunctional lipid transporter that facilitates long-chain fatty acid uptake and orchestrates metabolic signaling in energy-demanding tissues. Recent studies have uncovered site-specific palmitoylation as a crucial post-translational modification that governs CD36 subcellular trafficking, stabilizing its localization within lipid rafts and regulating its endocytic recycling between the plasma membrane, endosomes, and lipid droplets. This dynamic palmitoylation-depalmitoylation cycle enables CD36 to spatially and temporally couple lipid transport with signal transduction in response to nutritional and hormonal cues. Disruption of this regulatory axis leads to aberrant fatty acid uptake, inflammatory activation, and metabolic dysfunction, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and atherosclerosis. Here, we delineate the mechanistic basis of CD36 palmitoylation-dependent trafficking and its integration with lipid handling, signal transduction, and disease pathogenesis. Targeting this regulatory interface offers a promising avenue for therapeutic intervention in metabolic disorders.