EGFR: A promising therapeutic target in renal fibrosis
- 1Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, School of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia, 750004, China
- 2School of Health, Sichuan Vocational and Technical College, Suining, 629000, China
- 3School of Chemistry and Chemical Engineering, Xianyang Normal University, Xianyang, Shaanxi, 712000, China; Corresponding author.
Abstract
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.
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BibTeX
@article{cai2026egfr,
title = {{EGFR: A promising therapeutic target in renal fibrosis}},
author = {Yangyang Cai and Qian Wu and Fang Dou and Xia Yang and Jie Cui and Rui Wang and Yalong Feng and Kai Ji and Hua Chen},
journal = {Experimental and Molecular Pathology},
year = {2026},
month = oct,
doi = {10.1016/j.yexmp.2026.105089},
url = {https://doi.org/10.1016/j.yexmp.2026.105089},
note = {CC BY},
}
RIS
TY - JOUR
TI - EGFR: A promising therapeutic target in renal fibrosis
AU - Yangyang Cai
AU - Qian Wu
AU - Fang Dou
AU - Xia Yang
AU - Jie Cui
AU - Rui Wang
AU - Yalong Feng
AU - Kai Ji
AU - Hua Chen
PY - 2026
DA - 2026/10/30
JO - Experimental and Molecular Pathology
DO - 10.1016/j.yexmp.2026.105089
UR - https://doi.org/10.1016/j.yexmp.2026.105089
AB - 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.
SN - 1096-0945
ER -