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Through the downstream cAMP\u2013protein 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\u20139) and one soluble isoform (ADCY10), all of which exhibit tissue\u2011specific distribution, distinct regulatory mechanisms, and non\u2011redundant functions in core metabolic organs. Compelling evidence from gene\u2011edited animal models, functional validation studies, and multi\u2011ethnic 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\u2011associated 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\u2011targeted agents and highlights unresolved challenges and future directions. Particular emphasis is given to recent structural biology breakthroughs, genetic evidence from diverse populations, and isoform\u2011specific therapeutic strategies, with the aim of providing a theoretical basis for mechanistic research and the development of targeted therapeutics for metabolic diseases.<\/jats:p>","DOI":"10.1002\/jcp.70216","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T05:32:44Z","timestamp":1786685564000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adenylyl Cyclase (ADCY) Protein Family: Molecular Mechanisms and Therapeutic Potential in Glucose and Lipid Metabolism and Feeding Regulation"],"prefix":"10.1002","volume":"241","author":[{"given":"Shaohong","family":"Wu","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Jinan University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxue","family":"Chen","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Jinan University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Clinical Medicine Qilu Medical University Zibo China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinshan","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Jinan University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"e_1_2_15_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/biology9090244"},{"key":"e_1_2_15_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph17060736"},{"key":"e_1_2_15_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2005.02.029"},{"key":"e_1_2_15_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2017.06.014"},{"key":"e_1_2_15_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2017.112"},{"key":"e_1_2_15_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0043-x"},{"key":"e_1_2_15_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2018.03.002"},{"key":"e_1_2_15_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox13060743"},{"key":"e_1_2_15_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118460"},{"key":"e_1_2_15_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2023.119585"},{"key":"e_1_2_15_12_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.113.208157"},{"key":"e_1_2_15_13_1","article-title":"The Bile Acid Receptor TGR5 Regulates the Hematopoietic Support Capacity of the Bone Marrow Niche","volume":"13","author":"Alonso\u2010Calleja A.","year":"2024","journal-title":"eLife"},{"key":"e_1_2_15_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100606"},{"issue":"5","key":"e_1_2_15_15_1","article-title":"Targeting Soluble Adenylyl Cyclase for On\u2010Demand Contraception","volume":"41","author":"Gardner E. 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