Conformation‐Selective Modulation of Glucocorticoid Receptor Signaling: Mechanisms and Pharmacological Implications

Glucocorticoids (GCs) remain frontline therapies for inflammatory diseases, yet long‐term use is constrained by severe metabolic side effects and variable responses—a paradox rooted in the classical transactivation/transrepression (TA/TR) dichotomy. This binary model has proven insufficient to explain GC pharmacology. Emerging structural and genomic evidence redefines the glucocorticoid receptor (GR) as a conformationally dynamic integrator. Ligand structure dictates receptor folding and allosteric modulation, while chromatin accessibility, DNA response elements, coregulator recruitment, and post‐translational modifications collectively shape context‐dependent transcriptional outputs. This supports a paradigm shift toward conformation‐selective GR pharmacology, where distinct receptor conformations encode graded transcriptional programs. In this review, we integrate structural biology and epigenomics to propose a unified framework explaining the persistent efficacy–toxicity uncoupling in GC therapy. We critically reassess prior strategies, including selective GR modulators (SEGRMs), and identify mechanistic bottlenecks—limited conformational selectivity and insufficient consideration of chromatin context—that hindered clinical translation. Emphasis is placed on emerging conformation‐biased ligands and systems pharmacology approaches that leverage GR plasticity for safer, precision therapy. This framework opens new avenues for rational design of next‐generation nuclear receptor‐targeted drugs.