The Bidirectional Interaction Between NF‐ <i>κ</i> B 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-<i>κ</i>B (NF-<i>κ</i>B). 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-<i>κ</i>B. This disinhibition results in sustained NF-<i>κ</i>B 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-<i>κ</i>B signaling interface as a critical and therapeutically targetable mediator of stress-induced carcinogenesis.