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Simple Summary: Lipocalin 2 (LCN2) is a proinflammatory mediator increased in the blood of patients with myeloproliferative neoplasms (MPN) and other hematologic malignancies, significantly contributing to MPN disease initiation and progression. Here, we investigated the underlying mechanisms of LCN2 overexpression in MPN. We found a strong correlation between BCR–ABL and JAK2V617F driver oncogenes and LCN2 expression. Furthermore, LCN2 expression is strongly induced by endoplasmic reticulum (ER) stress, independent of oncogenic kinase activity. We identified the IRE1–JNK–NF-κB–C/EBP axis as a major mediator of ER stress-induced LCN2 expression. Our findings provide novel insights into the regulation of LCN2 and present a basis for innovative, targeted treatment approaches in MPN. Lipocalin 2 (LCN2), a proinflammatory mediator, is involved in the pathogenesis of myeloproliferative neoplasms (MPN). Here, we investigated the molecular mechanisms of LCN2 overexpression in MPN. LCN2 mRNA expression was 20-fold upregulated in peripheral blood (PB) mononuclear cells of chronic myeloid leukemia (CML) and myelofibrosis (MF) patients vs. healthy controls. In addition, LCN2 serum levels were significantly increased in polycythemia vera (PV) and MF and positively correlated with JAK2V617F and mutated CALR allele burden and neutrophil counts. Mechanistically, we identified endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a main driver of LCN2 expression in BCR-ABL- and JAK2V617F-positive 32D cells. The UPR inducer thapsigargin increased LCN2 expression >100-fold, and this was not affected by kinase inhibition of BCR-ABL or JAK2V617F. Interestingly, inhibition of the UPR regulators inositol-requiring enzyme 1 (IRE1) and c-Jun N-terminal kinase (JNK) significantly reduced thapsigargin-induced LCN2 RNA and protein expression, and luciferase promoter assays identified nuclear factor kappa B (NF-κB) and CCAAT binding protein (C/EBP) as critical regulators of mLCN2 transcription. In conclusion, the IRE1–JNK-NF-κB–C/EBP axis is a major driver of LCN2 expression in MPN, and targeting UPR and LCN2 may represent a promising novel therapeutic approach in MPN. [ABSTRACT FROM AUTHOR]