Hypoxia-inducible factor-1α (HIF-1α) is widely distributed in human cells, and it can form different signaling pathways with various upstream and downstream proteins, mediate hypoxia signals, regulate cells to produce a series of compensatory responses to hypoxia, and play an important role in the physiological and pathological processes of the body, so it is a focus of biomedical research. In recent years, various types of HIF-1α inhibitors have been designed and synthesized and are expected to become a new class of drugs for the treatment of diseases such as tumors, leukemia, diabetes, and ischemic diseases. This article mainly reviews the structure and functional regulation of HIF-1α, the modes of action of HIF-1α inhibitors, and the application of HIF-1α inhibitors during the treatment of diseases.

Hypoxia and oxidative stress are the common causes of various types of kidney injury. During recent years, the studies on hypoxia inducible factor‐ (HIF‐) 1 attract more and more attention, which can not only mediate hypoxia adaptation but also contribute to profibrotic changes. Through analyzing related literatures, we found that oxidative stress can regulate the expression and activity of HIF‐1α through some signaling molecules, such as prolyl hydroxylase domain‐containing protein (PHD), PI‐3K, and microRNA. And oxidative stress can take part in inflammation, epithelial‐mesenchymal transition, and extracellular matrix deposition mediated by HIF‐1 via interacting with classical NF‐κB and TGF‐β signaling pathways. Therefore, based on previous literatures, this review summarizes the contribution of oxidative stress to HIF‐1‐mediated profibrotic changes during the kidney damage, in order to further understand the role of oxidative stress in renal fibrosis.

The increase of oxidative stress is one of the important characteristics of mammalian luteal regression. Previous investigations have revealed the essential role of reactive oxygen species (ROS) in luteal cell death during luteolysis, while it is unknown how ROS is regulated in this process. Considering the decrease of blood flow and increase of PGF_2α during luteolysis, we hypothesized that the HIF‐1α pathway may be involved in the regulation of ROS in the luteal cell of the late corpus luteum (CL). Here, by using a pseudopregnant rat model, we showed that the level of both HIF‐1α and its downstream BNIP3 was increased during luteal regression. Consistently, we observed the increase of autophagy level during luteolysis, which is regulated in a Beclin1‐independent manner. Comparing with early (Day 7 of pseudopregnancy) and middle CL (Day 14), the level of ROS was significantly increased in late CL, indicating the contribution of oxidative stress in luteolysis. Inhibition of HIF‐1α by echinomycin (Ech), a potent HIF‐1α inhibitor, ameliorated the upregulation of BNIP3 and NIX, as well as the induction of autophagy and the accumulation of ROS in luteal cells on Day 21 of pseudopregnancy. Morphologically, Ech treatment delayed the atrophy of the luteal structure at the late‐luteal stage. An in vitro study indicated that inhibition of HIF‐1α can also attenuate PGF_2α‐induced ROS and luteal cell apoptosis. Furthermore, the decrease of cell apoptosis can also be observed by ROS inhibition under PGF_2α treatment. Taken together, our results indicated that HIF‐1α signaling is involved in the regression of CL by modulating ROS production via orchestrating autophagy. Inhibition of HIF‐1α could obviously hamper the apoptosis of luteal cells and the process of luteal regression.

HIF-1α plays a crucial regulatory role in vascular calcification (VC), primarily influencing the osteogenic differentiation of VSMCs through oxygen-sensing mechanisms. Under hypoxic conditions, the stability of HIF-1α increases, avoiding PHD and VHL protein-mediated degradation, which promotes its accumulation in cells and then activates gene expressions related to calcification. Additionally, HIF-1α modulates the metabolic state of VSMCs by regulating the pathways that govern the switch between glycolysis and oxidative phosphorylation, thereby further advancing the calcification process. The interaction between HIF-1α and other signaling pathways, such as nuclear factor-κB, Notch, and Wnt/β-catenin, creates a complex regulatory network that serves as a critical driving force in VC. Therefore, a deeper understanding of the role and regulatory mechanism of the HIF-1α signaling during the development and progression of VC is of great significance, as it is not only a key molecular marker for understanding the pathological mechanisms of VC but also represents a promising target for future anti-calcification therapies.

The impact of ionizing radiation on the male reproductive system is gaining increasing attention, particularly when it comes to testicular damage, which may result in decreased sperm quality and hormonal imbalances. Finding effective protective measures to mitigate testicular damage caused by radiation has become a focal point in the biomedical field. S1P, an essential biological signaling molecule, has garnered significant interest due to its multiple roles in regulating cellular functions and its protective effects against radiation-induced testicular injury. S1P not only effectively reduces the generation of ROS induced by radiation but also alleviates oxidative stress by enhancing the activity of antioxidant enzymes. Furthermore, S1P inhibits radiation-induced cell apoptosis by regulating the expression of anti-apoptotic and pro-apoptotic proteins. Additionally, S1P alleviates radiation-induced inflammation by inhibiting the production of inflammatory factors, thereby further protecting testicular tissue. In summary, S1P effectively reduces radiation-induced testicular damage through multiple mechanisms, offering a promising therapeutic approach to safeguard male reproductive health. Future research should explore the specific mechanisms of action and clinical application potential of S1P, aiming to contribute significantly to the prevention and treatment of radiation damage.

Endometrial decidualization is a hormonally programmed differentiation and tissue-remodeling process that prepares the endometrium for embryo implantation and supports early pregnancy. It involves coordinated changes in endometrial stromal cells, the extracellular matrix, vascular function, metabolism, and local immune composition. Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor that responds to changes in tissue oxygenation and metabolic state. Evidence from endometrial stromal-cell models and reproductive tissues suggests that HIF-1α may participate in decidual cell differentiation, metabolic adaptation, angiogenic signaling, and immune regulation. However, the strength of evidence differs substantially among these processes, and findings from trophoblasts, placenta, immune cells, or non-reproductive tissues cannot automatically be interpreted as direct evidence for decidual stromal-cell mechanisms. This review summarizes current evidence for HIF-1α in endometrial decidualization, distinguishes direct endometrial findings from mechanistic extrapolation, and considers the interaction of HIF-1α with metabolic, vascular, immune, and epigenetic pathways. Overall, HIF-1α is best considered a context-dependent component of the decidualization network rather than an independent master regulator. Defining its cell-specific and temporal functions, including its relationship with HIF-2α, will be important for determining whether HIF-directed interventions can be developed without disrupting physiological reproductive adaptation.