<p>Ferroptosis is a novel form of programmed cell death that is distinct from apoptosis, necrosis, and autophagy (macroautophagy). It is characterized by alterations in intracellular iron levels and lipid peroxidation. Considering its close association with numerous diseases, the molecular mechanisms underlying cellular ferroptosis have recently emerged as a prominent research focus. Lipocalin 2 (LCN2) is a circulating protein involved in the regulation of diverse cellular processes in eukaryotes and is closely associated with ferroptosis. However, the modulation of ferroptosis by LCN2 exhibits significant tissue and disease specificity. This is not only attributed to the ability of LCN2 to mediate iron metabolism reprogramming, but also to its capacity to bidirectionally regulate oxidative stress and interact with multiple signaling pathways. Therefore, this review summarizes the mechanisms through which LCN2 contributes to ferroptosis and its tissue- and disease-specific regulatory functions. Additionally, the current status of the clinical translation of LCN2 as a biomarker and therapeutic target is explored.</p> Graphical abstract <p>• Lipocalin 2 (LCN2) bidirectionally regulates ferroptosis by modulating iron metabolism, oxidative stress, and interacting with complex signaling networks.</p> <p>• The regulation of ferroptosis by LCN2 exhibits tissue- and disease-specificity.</p> <p>• LCN2 is an outstanding biomarker and a potential therapeutic target in ferroptosis-related diseases.</p> <p></p>