ADCY4 encodes adenylate cyclase 4, a membrane-bound enzyme that catalyzes cAMP synthesis downstream of G-protein-coupled receptor signaling 1. The enzyme converts ATP to cAMP, which activates protein kinase A (PKA) and modulates various cellular responses 2. In immune homeostasis, ADCY4-generated cAMP suppresses caspase-11 inflammasome activation and pyroptosis through PKA-mediated inhibition of GSDMD cleavage, protecting against sepsis-induced lethality 2. ADCY4 functions as a tumor suppressor in breast cancer, where it inhibits cell proliferation, invasion, and metastasis by activating cAMP/PKA signaling, which subsequently inactivates FAK/AKT and ERK survival pathways 3. However, ADCY4 is frequently silenced by DNA methylation in multiple cancers including breast, lung, colorectal, and prostate cancers 45. High ADCY4 expression correlates with improved breast cancer patient survival 4. Additionally, ADCY4 has been identified as a differentially methylated gene in osteoarthritis and acute myocardial infarction, suggesting broader roles in inflammatory and metabolic disease pathogenesis 67. Epigenetic restoration of ADCY4 expression represents a potential therapeutic strategy for cancer treatment and chemosensitization 3.