Adenylyl Cyclase (ADCY) Protein Family: Molecular Mechanisms and Therapeutic Potential in Glucose and Lipid Metabolism and Feeding Regulation.

The adenylyl cyclase (ADCY) family comprises key signal transduction enzymes that catalyze the conversion of ATP to the second messenger cyclic adenosine monophosphate (cAMP). Through the downstream cAMP-protein kinase A (PKA) signaling pathway, this family exerts central regulatory effects on glucose and lipid homeostasis. In mammals, the ADCY family consists of nine transmembrane isoforms (ADCY1-9) and one soluble isoform (ADCY10), all of which exhibit tissue‑specific distribution, distinct regulatory mechanisms, and non‑redundant functions in core metabolic organs. Compelling evidence from gene‑edited animal models, functional validation studies, and multi‑ethnic genetic association analyses has demonstrated that dysfunction of specific ADCY isoforms is closely linked to the pathogenesis of obesity, type 2 diabetes mellitus (T2DM), metabolic dysfunction‑associated steatotic liver disease (MASLD), and other metabolic disorders. This review systematically summarizes the classification, structural characteristics, and multilayered regulatory mechanisms of the ADCY family, with a particular focus on the physiological and pathological roles of its isoforms in glucose metabolism, lipid metabolism, and feeding regulation. It also discusses recent advances in ADCY‑targeted agents and highlights unresolved challenges and future directions. Particular emphasis is given to recent structural biology breakthroughs, genetic evidence from diverse populations, and isoform‑specific therapeutic strategies, with the aim of providing a theoretical basis for mechanistic research and the development of targeted therapeutics for metabolic diseases.