EGFR as a context-dependent modulator of endothelial inflammation: A systematic review

Epidermal growth factor receptor (EGFR), a member of the ErbB family, regulates key cellular processes such as proliferation, survival, and differentiation, and participates in angiogenesis and pathological conditions, including cancer; however, its role in endothelial inflammation remains poorly understood. Based on the hypothesis that its dysregulation contributes to endothelial dysfunction through interactions with multiple signaling pathways, including NF-κB activation, ROS-mediated redox signaling, VEGF-dependent axes, and regulated cell death processes, this systematic review sought to evaluate and synthesize evidence on the molecular mechanisms underlying this process. The search was conducted in PubMed, Web of Science, Scopus, and the Cochrane Library, without time restriction, resulting in 236 records; after screening according to PRISMA, 10 studies were included. Taken together, the evidence suggests that EGFR may act as an integrator of stimuli derived from growth factors, cytokines, and mechanical stresses. Although the classical pathways associated with this receptor, RAS/RAF/MEK/ERK, PI3K/AKT, and JAK/STAT, are well established, the included studies highlight additional mechanisms, including NF-κB, p38, Gαq/11-GIT1-c-Src pathways. While there is convergence regarding increased endothelial permeability and pro-inflammatory signaling under sustained or dysregulated activation, the responses vary according to tissue, cell type, and experimental context, which may limit their strength and generalizability. Overall, these findings appear to indicate a context-dependent role of EGFR in endothelial inflammatory processes. Nevertheless, the heterogeneity among studies warrants cautious interpretation and highlights the need for comparative investigations to clarify the circumstances under which its modulation is protective or harmful.