C5AR1 (complement C5a receptor 1) is a G protein-coupled receptor that mediates inflammatory responses by binding the complement peptide C5a 1. The receptor operates through dual binding sites: a high-affinity extracellular N-terminal site and a transmembrane signaling site that activates G(i)/G(o) proteins and inhibits adenylate cyclase 2. C5AR1 stimulates chemotaxis, granule enzyme release, intracellular calcium mobilization, and superoxide production in immune cells 1. Beyond canonical plasma membrane signaling, C5AR1 functions intracellularly on mitochondrial membranes, where it regulates metabolic reprogramming and inflammatory output in macrophages 3. In the complement-mediated kidney disease context, C5a-C5aR1 axis activation promotes podocyte injury through Drp1-mediated mitochondrial fission 4. Clinically, C5AR1 antagonism shows therapeutic promise across multiple diseases. Avacopan, a selective C5aR1 inhibitor, achieved sustained remission superior to prednisone in ANCA-associated vasculitis at 52 weeks 5, and animal models confirm C5aR blockade protects against ANCA-related necrotizing glomerulonephritis 6. C5aR1 inhibition also attenuates neuroinflammation-driven cerebral edema following acute brain injury 7, suppresses ferroptosis-resistant glioblastoma progression 8, and reverses PARP inhibitor resistance in breast cancer by reprogramming tumor-associated macrophages 9.