Protein palmitoylation in disease: decoding its crosstalk with ubiquitination and phosphorylation for pathogenic...

Protein S-palmitoylation is a reversible lipid modification that governs protein stability, trafficking, and signaling. Rather than an isolated tag, it acts as a spatiotemporal routing signal within an integrated post-translational modification (PTM) network, engaging in three defined crosstalk modes with ubiquitination and phosphorylation: synergistic, antagonistic, and cascading. Although crosstalk with acetylation and myristoylation exists, this review focuses on the ubiquitination- and phosphorylation-centered networks most directly linked to palmitoylation in disease. The same palmitoylation event can stabilize or destabilize substrates, or activate or silence signaling, depending on the specific Zinc finger DHHC domain-containing protein (ZDHHC) isoform, subcellular location, local enzyme availability, and metabolic state. We further introduce the "PTM context signature", a four-variable predictive framework for disease-specific crosstalk outcomes. By dissecting palmitoylation-centered crosstalk through a disease-oriented lens, we examine how its dysregulation drives oncogenesis, inflammation, metabolic disorders, and neurodegeneration. We then translate these mechanistic principles into a network-centric therapeutic framework, evaluating ZDHHC-directed modulators, peptide-based interface disruptors, and crosstalk-informed combinations that target context-specific nodes and anticipate therapy resistance. Viewing palmitoylation as an integrated component of the cellular PTM network, rather than as an isolated lipid tag, provides a framework for understanding disease pathogenesis and for targeting PTM networks rather than single modifications.