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Summary: Epidermal growth factor receptor (EGFR) activation and lipocalin-2 (Lcn2) expression are frequently observed in the same pathological contexts, such as cancers or chronic kidney disease (CKD). However, the significance of this association is unknown. Here, we describe the role of Lcn2 in regulating EGFR trafficking. We show that Lcn2 increases EGFR cell surface abundance and is required for transforming growth factor α (TGF-α)-induced EGFR recycling to the plasma membrane and sustained activation. Lcn2 binds to the intracellular domain of EGFR in late endosomal compartments and inhibits its lysosomal degradation. Consistently, Lcn2 enhances EGFR-induced cell migration after TGF-α stimulation. In vivo, Lcn2 gene inactivation prevents EGFR recycling to the plasma membrane in an experimental model of CKD. Remarkably, this is associated with a dramatic decrease of renal lesions. Together, our data identify Lcn2 as a key mediator of EGFR trafficking processes. Hence, therapeutic inhibition of Lcn2 may counteract the deleterious effect of EGFR activation. : Yammine et al. propose lipocalin-2 (Lcn2) as a regulator of EGFR activity. By binding to TGF-α-activated EGFR intracellular domain, cytosolic Lcn2 enhances its recycling to the cell surface. This accounts for EGFR sustained activation leading to chronic kidney disease and makes Lcn2 a potential therapeutic target in this context. Keywords: EGFR, lipocalin-2, recycling, trafficking, chronic kidney disease