Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders.

The melanocortin-4 receptor (MC4R) is a key regulator of energy balance and a potential target for weight management. Early drug discovery endeavors were hindered by incomplete understanding of its signal transduction mechanisms and broad activation of Gs pathways. Recent advances indicate that MC4R elicits multiple intracellular responses, with Gq/11 signaling in the paraventricular nucleus (PVN) neurons playing a central role in appetite suppression. High-resolution cryo-electron microscopy structures of MC4R, such as the setmelanotide-MC4R-Gq complex reported here, provide valuable insights into ligand binding, receptor activation, and biased signaling, thereby enabling the design of more selective agonists with improved safety profiles. Combination therapies targeting MC4R alongside glucagon-like peptide-1 mimetics and other agents regulating metabolic pathways have shown promise to enhance weight loss. MC4R modulators are also implicated in treating other disorders, including melanocortin signaling dysfunction. These progresses call for renewed efforts in developing the next-generation MC4R-based therapies against metabolic diseases.