The palmitoylation code in cell death signaling: from molecular mechanisms to therapeutic opportunities

The dynamic lipid modification known as protein palmitoylation is essential for modulating protein activity and subcellular distribution. This process is increasingly recognized as a pivotal molecular mechanism governing the balance between cellular survival and death. This paper explores the molecular regulation of palmitoylation within diverse pathways of regulated cell death, for instance, in necroptosis, ferroptosis, pyroptosis, and apoptosis. The core findings indicate that by controlling the stability, membrane anchoring, and interactions of key signaling proteins, palmitoylation can precisely regulate the ultimate fate of the cell. Additionally, the dysregulation of palmitoylation is closely linked to the pathogenesis of major human diseases, including cancer, neurodegenerative disorders, and inflammatory diseases. For instance, the process can display a dual role in tumor progression, acting to either promote or inhibit it. Concurrently, it is essential for the inflammatory signaling in pyroptosis and for mounting a cellular defense against ferroptosis. A deeper understanding of these regulatory networks provides highly promising therapeutic targets for disease intervention. Targeting the activity of specific palmitoylation-related enzymes has emerged as an innovative strategy for developing novel therapies for a range of diseases, demonstrating significant clinical translational potential.