Revisiting pharmacological actions of disodium cromoglycate in light of GPR35: New therapeutic contexts for classical drugs.

Mast cell stabilizers such as disodium cromoglycate have been used for decades as prophylactic anti-allergic agents, yet their molecular targets remained unknown, and their intracellular mechanisms were long debated. Identification of GPR35 as a receptor engaged by multiple mast cell stabilizers provided a new framework to reinterpret classical pharmacology. Here, historical and recent evidence linking mast cell stabilizers to GPR35 is integrated and pharmacological characteristics of GPR35 are described in the context of species difference and intracellular signaling. GPR35 is expressed in epithelial, myeloid, and sensory neuronal compartments, raising the possibility that some "mast cell stabilizer" phenotypes reflect actions outside mast cells. This perspective becomes particularly relevant in inflammatory bowel disease, where genetic studies support a protective role for GPR35 in mucosal homeostasis, potentially through epithelial barrier integrity and macrophage function. Emerging data also implicate GPR35 in neurogenic inflammation/itch pathways and vascular remodeling, further broadening therapeutic considerations. Accumulating evidence suggests that GPR35 exhibits physiologically relevant constitutive activity, implying that the GPR35-mediated actions may depend not only on ligand engagement but also on expression levels and cellular states. Implications for drug repositioning of mast cell stabilizers and future GPR35-targeted therapeutics are also discussed.