Palmitic acid activates c-Myc via dual palmitoylation-dependent pathways to promote colon cancer.

c-Myc is broadly hyperactivated in colon cancer, yet the mechanisms sustaining its transcriptional activation remain elusive. Here we identify palmitic acid (PA) as a metabolite cue that activates c-Myc via dual palmitoylation-dependent pathways operating across tumor initiation and progression. In colitis models, PA-rich diets exacerbate inflammation and enrich MYC target programs without increasing Myc mRNA. Mechanistically, the palmitoyltransferase ZDHHC9, upregulated by IL-1β, directly palmitoylates c-Myc at C171, enhancing c-Myc/MAX dimerization and transcriptional activity; genetic or pharmacologic inhibition diminishes c-Myc palmitoylation and target gene expression. During tumor progression, c-Myc transactivates FATP2, increasing PA uptake and reinforcing c-Myc palmitoylation, thereby establishing a feedforward loop and metabolic addiction to PA. Functionally, PA accelerates xenograft growth, whereas targeting ZDHHC9 and FATP2 inhibits c-Myc function to suppress tumor burden. These findings uncover metabolite-driven control of c-Myc through palmitoylation and highlight ZDHHC9/FATP2 as actionable vulnerabilities for colon cancer treatment.