[8][9] The dysregulation and overexpression of HIF1A by either hypoxia or genetic alternations have been heavily implicated in cancer biology, as well as a number of other pathophysiologies, specifically in areas of vascularization and angiogenesis, energy metabolism, cell survival, and tumor invasion.

[27] HIF-1 is known to induce transcription of more than 60 genes, including VEGF and erythropoietin that are involved in biological processes such as angiogenesis and erythropoiesis, which assist in promoting and increasing oxygen delivery to hypoxic regions.

[27] In accordance with its dynamic biological role, HIF-1 responds to systemic oxygen levels by undergoing conformational changes, and associates with HRE regions of promoters of hypoxia-responsive genes to induce transcription.

Under normoxic conditions, VHL-mediated ubiquitin protease pathway rapidly degrades HIF1A; however, under hypoxia, HIF1A protein degradation is prevented and HIF1A levels accumulate to associate with HIF1B to exert transcriptional roles on target genes [34][35] Enzymes prolyl hydroxylase (PHD) and HIF prolyl hydroxylase (HPH) are involved in specific post-translational modification of HIF1A proline residues (P402 and P564 within the ODD domain), which allows for VHL association with HIF1A.

[30][36] The hydroxylated proline residue of HIF1A is then recognized and buried in the hydrophobic core of von Hippel-Lindau tumor suppressor protein (VHL), which itself is part of a ubiquitin ligase enzyme.

[57] Based on the patent-pending HSF ("HIF strengthening factor") active ingredient, products have been developed that are supposed to promote skin and hair regeneration.

[67][68] HIF1A overexpression is heavily implicated in promoting tumor growth and metastasis through its role in initiating angiogenesis and regulating cellular metabolism to overcome hypoxia.

[10] Significant HIF1A expression has been noted in most solid tumors studied, which include cancers of the gastric, colon, breast, pancreas, kidneys, prostate, ovary, brain, and bladder.

[77] Moreover, despite histologically-determined low-grade, lymph-node negative breast tumor in a subset of patients examined, detection of significant HIF1A expression was able to independently predict poor response to therapy.

HIF-1α (Hypoxia-Inducible Factor-1 Alpha) is a critical regulator of cellular responses to hypoxia and plays dual roles in both adaptive survival and pathological injury during stroke.

In the event of an ischemic stroke, reduced cerebral blood flow creates a hypoxic environment that stabilizes HIF-1α by preventing its usual proteasomal degradation.

[86] This stabilization allows HIF-1α to dimerize with HIF-1β, forming the active HIF-1 transcription complex, which then binds to hypoxia-response elements (HREs) in the DNA to regulate a broad array of genes.

It enhances glycolysis by increasing the expression of glucose transporters (such as GLUT1) and key glycolytic enzymes (like PDK1), thereby facilitating anaerobic ATP production to maintain neuronal metabolism.

The factor also promotes erythropoiesis by stimulating erythropoietin (EPO) production, thereby improving oxygen delivery and exerting direct neuroprotective and anti-apoptotic effects.

Although VEGF-induced angiogenesis is beneficial for restoring blood flow, excessive VEGF can increase vascular permeability, leading to blood-brain barrier (BBB) disruption, cerebral edema, and the infiltration of inflammatory cells.

[92] The reliance on glycolytic metabolism during hypoxia also leads to lactic acid accumulation, which lowers pH and induces acidotoxicity, thereby compounding neuronal injury.

However, if activation persists into the subacute or chronic phase, the shift towards pro-inflammatory and pro-apoptotic pathways can worsen outcomes by promoting BBB breakdown and neuronal death.

[96] Conversely, in the acute phase, strategies aimed at inhibiting HIF-1α activity (using approaches like siRNA or small molecule inhibitors) may help to reduce edema, inflammation, and apoptosis.

Ultimately, achieving the correct spatiotemporal modulation of HIF-1α represents a promising strategy for developing targeted therapies to improve outcomes in stroke patients.