ZDHHC21 is a palmitoyltransferase that catalyzes S-palmitoylation of diverse protein substrates, with emerging roles in hematologic malignancies, neuropsychiatric disease, and sepsis complications. Beyond its established functions palmitoylating sex steroid hormone receptors and regulating membrane targeting 1, ZDHHC21 has been identified as a critical regulator of oxidative phosphorylation in acute myeloid leukemia (AML) through palmitoylation of mitochondrial adenylate kinase 2 (AK2), with ZDHHC21 inhibition inducing myeloid differentiation and suppressing drug-resistant leukemia stem cells 2. In diffuse large B-cell lymphoma, ZDHHC21 acts conversely as a tumor suppressor by mediating fatty acid synthase (FASN) palmitoylation, reducing FASN stability and lipogenesis 3. ZDHHC21 regulates serotonin 5-HT1A receptor palmitoylation in brain, with reduced ZDHHC21 expression and attenuated receptor palmitoylation observed in major depressive disorder and depression-like animal models 4. In sepsis pathology, ZDHHC21 mediates palmitoylation of STING and TRIM47, promoting pyroptosis and impairing autophagy respectively, contributing to acute lung injury and respiratory distress syndrome [PMID:41460311; 53]. Additionally, ZDHHC21 dynamically regulates TRPV2 ion channel palmitoylation in microglia, affecting amyloid-β phagocytosis in Alzheimer's disease 6. These diverse substrates position ZDHHC21 as a therapeutic target across multiple disease contexts.