In conclusion, we demonstrate that NAFLD enhances de novo palmitate synthesis in metastatic CRC cells and promotes CRLM via palmitoylation-dependent EGFR stabilization and PM localization, and that orlistat could be a promising adjuvant drug for suppressing NAFLD-induced CRLM and has synergistic effects with chemotherapy (Fig. 8). The gene discussed is EGFR; the disease is metabolic dysfunction-associated steatotic liver disease.