EGFR: A promising therapeutic target in renal fibrosis

Renal fibrosis represents the final common pathway in the progression of chronic kidney disease (CKD), characterized by excessive deposition of extracellular matrix (ECM) and progressive disruption of renal architecture. To date, no approved therapy can fully reverse established or advanced fibrosis. This review comprehensively summarizes the molecular mechanisms through which epidermal growth factor receptor (EGFR) signaling contributes to renal fibrosis and critically evaluates the therapeutic potential of EGFR-targeted interventions. Accumulating evidence reveals a context-dependent dual role for EGFR in kidney pathophysiology: transient EGFR activation supports epithelial repair following acute kidney injury, whereas sustained or dysregulated EGFR signaling promotes maladaptive repair and fibrogenesis. Mechanistically, persistent EGFR activation potentiates TGF-β/Smad signaling, activates mitogen-activated protein kinase (MAPK) cascades, promotes G2/M cell-cycle arrest and partial epithelial–mesenchymal transition (p-EMT) in tubular epithelial cells, and exacerbates inflammatory and oxidative responses involving nuclear factor kappa B (NF-κB), the NLRP3 inflammasome, and reactive oxygen species (ROS). Importantly, p-EMT in renal fibrosis is increasingly viewed as a profibrotic epithelial reprogramming state that impairs regenerative capacity and enhances paracrine signaling to interstitial fibroblasts rather than necessarily reflecting complete conversion of tubular epithelial cells into matrix-producing myofibroblasts. Together with metabolic dysfunction, these interconnected processes sustain fibroblast activation and pathological ECM accumulation. Current therapeutic strategies targeting EGFR include synthetic small-molecule inhibitors, natural bioactive compounds, and biological approaches. Although pharmacological EGFR inhibition demonstrates antifibrotic efficacy in preclinical models, clinical translation remains limited by systemic toxicity, insufficient renal specificity, and the absence of direct clinical validation in renal fibrosis. Overall, EGFR functions as a context-dependent molecular switch linking adaptive renal repair to maladaptive fibrotic remodeling. Future therapeutic development should therefore prioritize selective modulation of pathological EGFR activity and kidney-targeted delivery strategies that preserve beneficial repair-associated signaling while minimizing systemic toxicity.