Targeting Nur77 in Fibrosis and Aging: Context‐ and Stage‐Specific Molecular Mechanisms and Therapeutic Strategies

ABSTRACT

Fibrosis represents the end‐stage manifestation of numerous chronic diseases, characterized by persistent inflammatory cell infiltration, fibroblast‐to‐myofibroblast transition, and excessive extracellular matrix (ECM) deposition. This pathological process significantly contributes to the progression of chronic conditions and age‐related organ dysfunction. Nur77 (also designated as NR4A1, NGFI‐B, or TR3), an immediate‐early response gene product, is rapidly activated by diverse stimuli including growth factors, inflammatory signals, cytokines, and cellular stress. Emerging evidence establishes Nur77 as a critical regulator of fibroblast dynamics, governing their activation, proliferation, migration, and ECM production. The functional significance of Nur77 in fibrotic pathogenesis has been demonstrated across multiple organ systems,particularly in the heart, liver, lungs, and kidneys, positioning it as a promising therapeutic target for antifibrotic interventions. This review systematically examines the mechanistic basis of Nur77 involvement in fibrosis, detailing its regulatory effects on immune and stromal cells through multiple signaling pathways. We further analyze its participation in fibrosis‐associated pathological processes and specific diseases, as well as explore the interconnection between aging and fibrosis, and assess the therapeutic potential of Nur77. Collectively, this synthesis underscores Nur77 as an emerging molecular target with substantial promise for combating fibrosis and aging‐related diseases.