GPR35 is a G protein-coupled receptor that serves as a promiscuous chemokine receptor with multiple physiological ligands. It binds tryptophan metabolite kynurenic acid (KYNA), lysophosphatidic acid (LPA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) with high affinity, triggering rapid intracellular signaling 1. Upon ligand binding, GPR35 couples to Gi/Go or G12/G13 heterotrimeric G proteins, modulating adenylate cyclase activity and Rho GTPase signaling 1. GPR35's primary functions span immune regulation and cardioprotection. KYNA binding promotes monocyte adhesion to vascular endothelium through Gi-mediated adenylate cyclase inhibition 1, while 5-HIAA signaling mediates neutrophil recruitment during inflammation and bacterial clearance 2. In macrophages, LPA activation induces TNF production via ERK and NF-κB pathways, promoting macrophage chemotaxis 3. During cardiac ischemia, KYNA-bound GPR35 traffics to mitochondrial membranes where it inhibits ATP synthase inhibitory factor (ATPIF1), promoting ATP synthase dimerization that preserves cellular energy 1. Clinically, GPR35 dysfunction associates with inflammatory bowel disease through altered macrophage TNF production 3, and emerging evidence links it to cancer progression and metastasis 4. GPR35 agonists represent promising therapeutic candidates for ischemic diseases, inflammatory disorders, and potentially cancer treatment.