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REVIEW ARTICLE

Hypoxia-inducible factor 1 alpha in cancer: Discovery, regulation, mechanism, and clinical impact

Bing-Hua Jiang1* Kibria Hassan1
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1 Department of Clinical Research and Translational Medicine, School of Convergence Medicine, Zhengzhou University, Zhengzhou, Henan, China
Received: 22 December 2025 | Revised: 29 May 2026 | Accepted: 29 May 2026 | Published online: 7 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 -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

Hypoxia-inducible factor 1 (HIF-1) has proven to be a master regulator of oxygen-homeostasis transcription, and its ubiquitous involvement in cancer progression has positioned it at the core of tumor biology and many other diseases. The review focuses on HIF-1’s role and regulation in cancer biology and therapeutic resistance, starting with its canonical regulation by oxygen, prolyl hydroxylases, and the von Hippel–Lindau tumor suppressor, followed by its non-hypoxic regulation of aberrant activation in malignancy, which is increasingly recognized. We rigorously examine the complex interplay of oncogenic signaling cascades, specifically prolyl hydroxylases, the von Hippel–Lindau tumor suppressor, phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin, and mitogen-activated protein kinase, alongside emerging roles of microRNA networks, growth factor signals, and reactive oxygen species in potentiating HIF-1α activity under normoxic conditions. Furthermore, we explore how environmental contaminants, including heavy metals, contribute to HIF-1α stabilization and subsequent carcinogenesis. A central focus is the functional significance of HIF-1α activation as a pivotal driver of angiogenesis, metabolic adaptation, invasive potential, and metastatic spread. Our analysis systematically delineates the context-dependent functions of HIF-1α across various human cancers, including breast, prostate, pulmonary, gastric, pancreatic, renal, and ovarian malignancies, as well as glioblastoma and osteosarcoma. This review underscores the established correlations between HIF-1α expression and aggressive tumor behavior, therapeutic resistance, and unfavorable patient prognoses. Lastly, we consider the current landscape of treatment approaches targeting HIF-1α, including direct small-molecule inhibitors and agents that disrupt its synthetic lethality or protein–protein interactions. By examining the molecular pathways, pathological effects, and clinical significance of HIF-1α, this review outlines the challenges and the potential to translate our comprehensive knowledge of this key transcription factor into next-generation cancer therapy.

Keywords
Angiogenesis
Cancer
Hypoxia
Hypoxia-inducible factor 1 alpha
Tumor microenvironment
Funding
None.
Conflict of interest
Bing-Hua Jiang serves as the Editor-in-Chief of this journal; however, he was not involved, directly or indirectly, in the editorial or peer- review process for this paper. The other authors have declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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