The Bidirectional Interaction Between NF-κB and Glucocorticoid Receptor: Underlying Mechanisms of Chronic Stress-Induced Pathology

Chronic stress is an established etiological factor for numerous pathologies, including cancer, yet the underlying molecular etiology remains incompletely understood. This review elucidates a critical molecular axis through which chronic stress promotes carcinogenesis via the bidirectional interaction between the glucocorticoid receptor (GR) and nuclear factor-κB (NF-κB). The review comprehensively details how chronic stress induces pathological GR signaling, characterized by post-translational modifications (PTMs), glucocorticoid (GC) resistance, and altered expression of receptor isoforms. This impairment of GR function leads to the disinhibition of proinflammatory transcription factor, NF-κB. This disinhibition results in sustained NF-κB hyperactivation, which orchestrates a protumorigenic microenvironment by driving genetic instability, immune evasion, uncontrolled proliferation, apoptosis resistance, angiogenesis, and metastasis. By providing an integrative synthesis of these interconnected pathways, this review offers a novel mechanistic framework that directly links the molecular consequences of chronic stress to the hallmarks of cancer. This work therefore establishes the GR/NF-κB signaling interface as a critical and therapeutically targetable mediator of stress-induced carcinogenesis.