Among the viral-mediated pandemics which have been spread worldwide within the last two decades rapidly, coronaviruses (CoVs) Cdependent outbreaks appear to be the most unfortunate implicated in lung pathology. genomic sequences concluding that although there are little specific differences in the RNA level discussing five just nucleotide sites, the band of 380 amino acidity substitutions in 2019 book beta-CoV (2019-nCoV) -phylogenetic?and RNA?series similarity in?96% with?BatCoV RaTG13-provides not merely structural divergence, but even more aggressive functional and clinic-pathogenic characteristics in infected communities [2] also. Regarding its hereditary proteins and substrate morphology, its RNA molecule (a big positive-sense RNA genome of around 30 kb) can be enclosed in a spherical-like glycoprotein envelope characterized by many spikes (S projections) on its surface that create a crown-like formation (corona). These modifications act as binding MAP2K2 tools for the corresponding membrane receptors of the host epithelial cells. The main receptor-binding loci that CoVs selectively use for cell invasion are human angiotensin-converting enzyme 2 (hACE2), CD209L, and dipeptyl peptidase 4 (DPP4/CD26) [3, 4]. hACE gene is located on chromosome 17 (band 17q23.3) encoding for a specific protein acting as zinc-based enzyme (metalloenzyme) in peptide hydrolysis. It is localized on the membrane surface of lung epithelia, vascular endothelial cells, and also on Leydig and kidney epithelial cells. In contrast, hACE2 gene is located on chromosome X (band Xp22.2) and its integral membrane protein product -that acts as carboxydipeptidase-shares an approximately 50% sequence homology with hACE. It is expressed mainly in heart, vascular endothelial cells, kidney and intestine cells and also in lung epithelia, critically in type II pneumonocytes of alveoli [5]. Recently, a molecular and structural analysis detected a mechanism of SARS-CoV-2 host cell penetration based on a novel furin-like (an enzyme, member of subtilisin-like proprotein convertase family) cleavage site on S1/S2 spike functional subunits that interacts directly with hACE2 [6, 7]. Interestingly, furin (band 15q26.1) expression is elevated in lung epithelia. In fact, the S1 subunit represents the main receptor-binding domain (RBD), whereas the S2 subunit is involved in membrane fusion. hACE2 receptor recognition and binding Atractylenolide I exposes rapidly virus transmissibility in human targets. Inhibition strategies are based on SARS-CoV-2 polyclonal antibodies preventing the S1/S2 furin cleavage/ hACE2 conjunction that promotes cell entry. Similarly, furin has been found to be a significant molecule as protease for providing proteolytic cleavage of Human Immunodeficiency Virus (HIV) protein precursor subunits (GP160 to GP120-GP41) before viral particles reconstruction in the Golgi apparatus [8]. Focused on patients that suffer from hematologic malignancies and especially in hematopoietic stem cell transplant recipients (HSCT), CoVs-dependent upper and lower respiratory tract infection is a severe complication, although that there are controversial data regarding the sequence and localization of the infection. A study group based on bronchoalveolar lavage (BAL) sample strain-specific polymerase chain reaction (ss-PCR) analysis reported significant proportions of CoVs genome presence in patients with lower respiratory system nonmalignant lesions (pneumonia) [9]. Additionally, they demonstrated that CoVs – connected mortality rates had been similar to additional copathogens (ie influenza pathogen) but a growing need for air source was also noticed reflecting the severe nature from the disease. As opposed to the prior released data, another research group analyzed by PCR nasopharyngeal and BAL liquid samples and recognized high prices of CoVs genomes correlated with top respiratory system lesions in comparison to limited Atractylenolide I pneumonia instances [10]. Both Atractylenolide I of the prior studies are described the crucial air supply in serious lung lesions mediated by CoV disease. And this can be a key-point not merely in the medical but also in the molecular level. S furin-mediated cleavage combined with hACE conversation leads to cell membrane penetration by SARS-CoV-2 but hypoxia signaling pathways deregulation seem to be also critical for the aggressive phenotype of the current contamination. Interestingly, a molecular study co-analyzing hACE2 and Mas receptor (MasR) in CD34+ hematopoietic stem/progenitor cells (HSPCs) concluded that both of them are involved and upregulated?in the hypoxic stimulation of the examined cell series [11]. Additionally, another important clinicopathological and molecular (RNA/ oligonucleotide-based microarrays) analysis investigated the role of monocytes/macrophages motivation and pulmonary fibrosis development in SARS-CoV – mediated pneumonia. The study group observed that genes responsible for intracellular oxygen homeostasis (normoxia/hypoxia/hyperoxia) were over activated and highly?expressed even in the first day of infection in the corresponding cell populations [12]. Interestingly, furin interacts with genes involved in hypoxia regulation regarding normal and cancerous cells [13]. Additionally, the interferon-induced Guanylate-Binding Proteins (GBPs) -especially 2/5 C inhibit furin-based envelope protein cleavage in a variety of viruses including HIV, Measles, Zika, and also Influenza A type, whereas Phoshpofurin Acidic Cluster Sorting Protein 1 (PACS1) strongly interacts with furin in trans-Golgi network [14]. Based on these continually updated molecular data we suggest that Vascular Endothelial Growth Factor/receptor (VEGF- band 6p21.1 /VEGFR), Mas receptor (MasR-6q25.3) and Hypoxia – Inducible Factor 1-alpha (HIF-1a – band14q23.2) should be analyzed in conjunction with hACE2 and Furin/GBP/PACS.