Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation Hypoxia-inducible factor-1 (HIF-1) is a key regulator of oxygen homeostasis in cells, functioning as a transcription factor that regulates the expression of genes involved in oxygen homeostasis in response to hypoxia. HIF-1 plays a crucial role in the hypoxic response and oxygen metabolism, contributing to tumor development and progression. The expression of the HIF-1α subunit is significantly upregulated in cancer cells, promoting tumor survival through multiple mechanisms. HIF-1 also contributes to cancer progression by influencing cell division, survival, proliferation, angiogenesis, and metastasis. Additionally, HIF-1 regulates cellular metabolic pathways, particularly anaerobic glucose metabolism. Given its significant role in cancer development and progression, HIF-1 has become an intriguing therapeutic target for cancer research. Several compounds targeting HIF-1-associated processes are now being used to treat different types of cancer. This review outlines emerging therapeutic strategies that target HIF-1 as well as the relevance and regulation of the HIF-1 pathways in cancer. Moreover, it addresses the employment of nanotechnology in developing these promising strategies. HIF-1 consists of three isoforms: HIF-1, HIF-2, and HIF-3. Each isoform is composed of a dimeric configuration comprising an alpha (α) subunit sensitive to oxygen and a beta (β) subunit insensitive to oxygen. HIF-1α and HIF-2α play crucial roles in the regulation of cellular oxygen homeostasis, while the function of HIF-3 remains less well defined. The HIF-1α subunit is regulated by oxygen availability, with its degradation occurring via the ubiquitin–proteasome pathway under normoxic conditions. In hypoxic conditions, HIF-1α remains stable and accumulates in the cytosol, relocating to the nucleus and binding with HIF-1β to form a functional heterodimer. This heterodimer regulates target gene transcription by recruiting p300/CBP co-activators and forming a functional HIF transcription complex. The complex binds to specific DNA sequences called hypoxia response elements found in the promoter regions of target genes, activating the transcription of target genes related to oxygen homeostasis, angiogenesis, glycolysis, tumor survival, and metastasis. HIF-1α plays a crucial role in cancer by influencing cell division and proliferation. In cases of severe hypoxia, HIF-1α can cause cell cycle arrest by suppressing c-Myc and increasing p21 levels. HIF-1α also plays a role in cell proliferation and survival. Hypoxia generally inhibits cell proliferation due to the increased oxygen demands associated with higher cell numbers,Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation Hypoxia-inducible factor-1 (HIF-1) is a key regulator of oxygen homeostasis in cells, functioning as a transcription factor that regulates the expression of genes involved in oxygen homeostasis in response to hypoxia. HIF-1 plays a crucial role in the hypoxic response and oxygen metabolism, contributing to tumor development and progression. The expression of the HIF-1α subunit is significantly upregulated in cancer cells, promoting tumor survival through multiple mechanisms. HIF-1 also contributes to cancer progression by influencing cell division, survival, proliferation, angiogenesis, and metastasis. Additionally, HIF-1 regulates cellular metabolic pathways, particularly anaerobic glucose metabolism. Given its significant role in cancer development and progression, HIF-1 has become an intriguing therapeutic target for cancer research. Several compounds targeting HIF-1-associated processes are now being used to treat different types of cancer. This review outlines emerging therapeutic strategies that target HIF-1 as well as the relevance and regulation of the HIF-1 pathways in cancer. Moreover, it addresses the employment of nanotechnology in developing these promising strategies. HIF-1 consists of three isoforms: HIF-1, HIF-2, and HIF-3. Each isoform is composed of a dimeric configuration comprising an alpha (α) subunit sensitive to oxygen and a beta (β) subunit insensitive to oxygen. HIF-1α and HIF-2α play crucial roles in the regulation of cellular oxygen homeostasis, while the function of HIF-3 remains less well defined. The HIF-1α subunit is regulated by oxygen availability, with its degradation occurring via the ubiquitin–proteasome pathway under normoxic conditions. In hypoxic conditions, HIF-1α remains stable and accumulates in the cytosol, relocating to the nucleus and binding with HIF-1β to form a functional heterodimer. This heterodimer regulates target gene transcription by recruiting p300/CBP co-activators and forming a functional HIF transcription complex. The complex binds to specific DNA sequences called hypoxia response elements found in the promoter regions of target genes, activating the transcription of target genes related to oxygen homeostasis, angiogenesis, glycolysis, tumor survival, and metastasis. HIF-1α plays a crucial role in cancer by influencing cell division and proliferation. In cases of severe hypoxia, HIF-1α can cause cell cycle arrest by suppressing c-Myc and increasing p21 levels. HIF-1α also plays a role in cell proliferation and survival. Hypoxia generally inhibits cell proliferation due to the increased oxygen demands associated with higher cell numbers,