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Figure 3. Palmitoylation coordinates EGFR membrane dynamics and organelle-specific signaling. Catalyzed by DHHC-family palmitoyltransferases (such as DHHC13 and DHHC20), palmitoylation at specific cysteine residues critically regulates EGFR subcellular localization. Palmitoylation anchors EGFR to the plasma membrane through the ARF6-dependent sorting pathway. However, palmitoylation at different cysteines elicits distinct functional outcomes: palmitoylation at C1025 inhibits Grb2 binding and downstream signaling, whereas palmitoylation at C1122 promotes endocytosis and subsequent lysosomal degradation. Meanwhile, FASN-mediated palmitoylation at C797 facilitates both mitochondrial translocation - enhancing mitochondrial fusion and cell survival via the PHB2/OPA1 axis - and nuclear import, thereby coordinating metabolic adaptation and proliferation. Created in BioRender. LIAN, J. (2026) https://BioRender.com/ivso7d7. EGFR: Epidermal growth factor receptor; ARF6: ADP-ribosylation factor 6; Grb2: growth factor receptor-bound protein 2; FASN: Fatty Acid Synthase; PHB2: prohibitin 2; OPA1: optic atrophy 1; P-AKT: phosphorylated protein kinase B; SREBP1: sterol regulatory element-binding protein 1.