BACKGROUND Despite the well-established epidemiological association between diabetic kidney disease (DKD) and coronary artery disease (CAD) in patients with T2DM, which reflects a core feature of cardiovascular-kidney-metabolic (CKM) syndrome, the underlying molecular mechanisms connecting these 2 conditions remain unclear. Within this integrated pathophysiological framework, the potential role of lipocalin-2 (LCN2) was investigated. MATERIAL AND METHODS A total of 917 participants with T2DM were stratified into an overall cohort and a BMI-, age-, and sex-matched sub-cohort. Serum LCN2 levels were measured. Immunohistochemistry was performed on cardiac and renal tissues from high-fat diet/streptozotocin-induced diabetic mice. Renal tubular (HK-2) and cardiomyocyte (H9c2) cells were treated with recombinant LCN2 to assess inflammatory responses. RESULTS DKD severity was identified as an independent risk factor for CAD in patients with T2DM. Serum LCN2 levels were significantly elevated in patients with DKD or CAD, and were closely correlated with DKD severity and B-type natriuretic peptide levels. Logistic regression analysis further indicated that an elevated serum LCN2 level served as an independent risk factor for the presence of DKD or CAD. Importantly, mediation analysis revealed that increased serum LCN2 may partially mediate the bidirectional association between DKD and CAD. Consistent with these clinical findings, animal experiments demonstrated concurrent upregulation of LCN2 in both the heart and kidney tissues of diabetic mice. Recombinant LCN2 dose-dependently increased interleukin-6 and tumor necrosis factor-a mRNA expression in HK-2 and H9c2 cells. CONCLUSIONS LCN2 may represent a potential biomarker and partial mediator between DKD and CAD in T2DM, potentially contributing to CKM-related organ crosstalk.