Taken together, our results not only reveal a novel biological function of ZDHHC21 as a tumor suppressor in DLBCL and identify it as a key regulator for FASN palmitoylation for the first time but also establish targeting ZDHHC21/FASN axis as a promising therapeutic strategy for patients with DLBCL. The gene discussed is ZDHHC21; the disease is diffuse large B-cell lymphoma.