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REVIEW ARTICLE

Polycythemia vera: Advances in molecular pathogenesis and emerging therapeutic strategies

Huan Zhang1 Shijie Zhang1 Jingxin Zhang1*
Received: 10 April 2026 | Revised: 19 June 2026 | Accepted: 22 June 2026 | Published online: 10 July 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Abstract

Polycythemia vera (PV) is a classic Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal erythrocytosis, expansion of myeloid lineages, and a high risk of thrombotic complications and progression to myelofibrosis or acute myeloid leukemia. The discovery of JAK2 mutations, particularly JAK2 V617F and exon 12 variants, has transformed the understanding of PV biology and established constitutive activation of Janus kinase (JAK)-signal transducer and activator of transcription signaling as a central pathogenic mechanism. However, PV pathogenesis extends beyond JAK2 dependency and involves aberrant activation of mitogen-activated protein kinase and phosphoinositide 3 kinase-protein kinase B pathways, epigenetic dysregulation, chronic inflammation, niche remodeling, and metabolic reprogramming. Increasing evidence suggests that PV evolves through stepwise clonal expansion, influenced by co-mutations in TET2, DNMT3A, ASXL1, and other regulators of chromatin and DNA methylation. These molecular insights have facilitated the development of targeted therapies, including JAK inhibitors, interferon formulations, epigenetic modulators, and metabolism-targeting strategies. Yet, major clinical challenges persist, including treatment resistance, intolerance to cytoreductive therapy, inadequate disease modification, and the prevention of thrombotic and fibrotic progression. This review synthesizes current knowledge on the molecular mechanisms underlying PV pathogenesis and discusses therapeutic strategies that integrate genetic, inflammatory, and metabolic vulnerabilities, highlighting future opportunities for personalized therapy and disease interception.

Keywords
Polycythemia vera
JAK-STAT signaling
Molecular pathogenesis
Therapeutic strategies
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 82570164, 81900111); Science and Technology Development Program of Henan Province (No. 252300421144).
Conflict of interest
The authors declare no conflicts of interest.
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