HIF-1α Pathway in COVID-19: A Scoping Review of Its Modulation and Related Treatments

Abstract

The COVID-19 pandemic, driven by SARS-CoV-2, has led to a global health crisis, highlighting the virus's unique molecular mechanisms that distinguish it from other respiratory pathogens. It is known that the Hypoxia-Inducible Factor 1α (HIF-1α) activates a complex network of intracellular signaling pathways regulating cellular energy metabolism, angiogenesis, and cell survival, contributing to the wide range of clinical manifestations of COVID-19, including Post-Acute COVID-19 Syndrome (PACS). Emerging evidence suggests that dysregulation of HIF-1α is a key driver of systemic inflammation, silent hypoxia, and pathological tissue remodeling in both the acute and post-acute phases of the disease. This scoping review was conducted following PRISMA-ScR guidelines and registered in INPLASY. It involved a literature search in Scopus and PubMed, supplemented by manual reference screening, with study selection facilitated by Rayyan software. Our analysis clarifies the dual role of HIF-1α, which may either worsen inflammatory responses and viral persistence or support adaptive mechanisms that reduce cellular damage. The potential for targeting HIF-1α therapeutically in COVID-19 is complex, requiring further investigation to clarify its precise role and translational applications. This review deepens the molecular understanding of SARS-CoV-2-induced cellular and tissue dysfunction in hypoxia, offering insights for improving clinical management strategies and addressing long-term sequelae.

Keywords: HIF-1α; SARS-CoV-2; hypoxia; inflammation; post-acute COVID-19 syndrome.

Figure 1

Flowchart following PRISMA-ScR.

Figure 2

The HIF pathway. Under normoxia, HIF-1α, the oxygen-sensitive subunit of the HIF heterodimer, experiences rapid proteasomal degradation. This process is facilitated by prolyl hydroxylase domain-containing enzymes (PHD1–3), which hydroxylate specific proline residues (Pro402/564 in HIF-1α) in an O₂-dependent manner. Hydroxylation enables recognition by the Von Hippel–Lindau (VHL), a component of the E3 ubiquitin ligase complex that marks HIF-1α for ubiquitination and subsequent degradation. In contrast, PHD activity is diminished under hypoxia due to limited O₂ availability, leading to the stabilization of HIF-1α. The stabilized subunit dimerizes with its constitutively expressed partner, HIF-1β and recruits transcriptional coactivators (p300/CBP) to hypoxia response elements (HREs), becoming activated to make the gene transcription.

Figure 3

The intersection of the angiogenesis process with the primary immune response. (1) The SARS-CoV-2 virus, upon entering the lung environment, binds to angiotensinogen-converting enzyme 2 (ACE-2) receptors, promoting an increase in angiotensin-2 concentration at the site due to competition for the ACE-2 receptor binding site. In response to the entry of the virus, macrophages of the M1 phenotype secrete pro-inflammatory cytokines, such as TNF-alpha, which bind to TNFR-1 receptors. Consequently, an intracellular signaling response occurs, which releases NF-kB from the inhibitory molecule IKB, allowing NF-kB to become active and enter the nucleus for its transcription action. (2) NF-kB acts by binding to the initiation site of the DNA molecule precursor of HIF-1α, inducing the transcription of HIF-1α RNA, which will then be translated into its protein form. In contact with the hypoxic environment, HIF-1α is not degraded and can enter the nucleus to act on the transcription of vascular endothelial growth factor RNA (VEGF-RNA) and its receptor, VEGFR-1-RNA. (3) VEGFR-1-RNA and VEGF-RNA, after being translated into the cytoplasm, will be able to exert the functions of membrane receptors and signaling proteins. VEGF will be secreted from the cell to act on similar cells or even on the cell that produced it.

Figure 4

Modulation of Viral Entry Through HIF-1α. ACE2—Angiotensin-Converting Enzyme 2; TMPRSS2—Transmembrane Serine Protease 2; HIF-1α—Hypoxia-Inducible Factor 1-alpha; PDK1—Pyruvate Dehydrogenase Kinase 1; PDH—Pyruvate Dehydrogenase; GLUT1—Glucose Transporter 1; HK2—Hexokinase 2; PFK-1—Phosphofructokinase-1; PKM2—Pyruvate Kinase M2; LDH-A—Lactate Dehydrogenase A; TCA—Tricarboxylic Acid (Krebs Cycle)); OXPHOS—Oxidative Phosphorylation.