Structure-guided modulation of the IL-4/IL-4Rα interface: molecular recognition, therapeutic antibodies, and small-molecule opportunities.

Interleukin-4 (IL-4) and its cognate receptor subunit IL-4 receptor alpha (IL-4Rα) constitute a central cytokine-receptor recognition system in type 2 inflammation and represent a challenging therapeutic target at the protein-protein interaction level. The IL-4/IL-4Rα interface is broad, highly polar, and dynamically linked to higher-order receptor assembly, creating substantial barriers to direct small-molecule modulation while also offering a valuable framework for structure-guided ligand design. This review examines the molecular basis of IL-4 signaling with emphasis on receptor recognition, interfacial hotspot residues, heterodimerization with γc or IL-13Rα1, and the structural determinants that govern downstream pathway activation. Clinically validated antibodies targeting IL-4 or IL-4Rα are discussed as important examples of successful interface-directed modulation and as benchmarks for target validation. Particular attention is then given to emerging small-molecule strategies aimed at perturbing IL-4-centered signaling, including direct and indirect modulators, while macrocycles are briefly considered as complementary non-antibody modalities for difficult cytokine-receptor PPI surfaces. By positioning the IL-4/IL-4Rα system as a defined and chemically challenging bioorganic target, this review highlights how biomolecular recognition, interfacial topology, and druggability considerations can inform future efforts to develop next-generation modulators of cytokine-receptor signaling. The article therefore provides a chemistry-oriented perspective on therapeutic intervention at a biologically important immune interface.