Hypoxia signaling in human health and diseases: implications and prospects for therapeutics

Abstract

Molecular oxygen (O2) is essential for most biological reactions in mammalian cells. When the intracellular oxygen content decreases, it is called hypoxia. The process of hypoxia is linked to several biological processes, including pathogenic microbe infection, metabolic adaptation, cancer, acute and chronic diseases, and other stress responses. The mechanism underlying cells respond to oxygen changes to mediate subsequent signal response is the central question during hypoxia. Hypoxia-inducible factors (HIFs) sense hypoxia to regulate the expressions of a series of downstream genes expression, which participate in multiple processes including cell metabolism, cell growth/death, cell proliferation, glycolysis, immune response, microbe infection, tumorigenesis, and metastasis. Importantly, hypoxia signaling also interacts with other cellular pathways, such as phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling, nuclear factor kappa-B (NF-κB) pathway, extracellular signal-regulated kinases (ERK) signaling, and endoplasmic reticulum (ER) stress. This paper systematically reviews the mechanisms of hypoxia signaling activation, the control of HIF signaling, and the function of HIF signaling in human health and diseases. In addition, the therapeutic targets involved in HIF signaling to balance health and diseases are summarized and highlighted, which would provide novel strategies for the design and development of therapeutic drugs.

PFC@O2 Targets HIF-1α to Reverse the Immunosuppressive TME in OSCC

“…As a key regulator of tumor hypoxia, HIF-1α is commonly highly expressed in solid tumors and is closely related to treatment failure and poor prognosis [ 7 , 11 , 12 ]. Similarly, the overexpression of HIF-1α was found in OSCC tissue specimens by IHC staining in our experiment.…”

“…While under hypoxia, HIF-1α will not be degraded and thus form HIF-1 to activate a panel of target genes, e.g., GLUT1 and CA IX [ 10 ]. HIF-1α has also been identified as the core factor of the hypoxia signaling pathway, which is involved in tumor angiogenesis, proliferation, invasion, metastasis, and even tumor immune suppression [ 5 , 11 , 12 ].…”

Role of HOXA9 in solid tumors: mechanistic insights and therapeutic potential

“…HIF-1α plays a vital role in physiological homeostasis. Take an example, research reported that HIF-1 reprogram glucose metabolism through regulating the transcription activity of glucose-associated genes such as GLUT1, PGK1, and PDK1 [ 44 ]. Zhou et al reported that loss of HOXA9 inhibits glycolysis in cSCC by hindering the binding of HIF-1α to its downstream targets such as HK2, GLUT1, and PDK1.…”

IL-17 signaling in skin repair: safeguarding metabolic adaptation of wound epithelial cells

“…HIF1α plays a crucial role in glycolysis in response to hypoxia. 4 HIF1α-mediated glycolysis is essential for efficient epithelization, as inhibiting glycolysis either pharmaceutically or genetically by deleting HIF1α expression delays wound epithelization. Using in vitro skin epithelial organoids and in vivo mouse models, the authors further show that IL-17A signaling enhances HIF1α expression through promoting HIF1α mRNA transcription rather than stabilizing HIF1α protein.…”

“…mTOR may drive HIF1α expression via multiple mechanisms at both transcriptional and translational level. 4 Using in vitro cultured cells and in vivo mouse models, Konieczny et al demonstrate that IL-17A binds to its receptor and signals to mTOR via ERK/AKT kinases. The activated mTOR signaling is essential for HIF1α expression, particularly under long-term hypoxia conditions.…”