Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) is a highly contagious coronavirus responsible for the life-threatening COVID-19. By December 2022, more than 650 million people were infected by SARS-COV-2, and it also caused more than 6 million deaths in more than 300 countries and regions around the world (WHO’s Monthly Operational Update on Health Emergencies, 2022). The risk of severe symptoms and complications, mortality and hospitalization in COVID-19 patients have been recently reported to be significantly increased due to some unhealthy pre-existing conditions, including hypertension, type 2 diabetes, and obesity (Fang et al., 2020). Compared with metabolic healthy patients, patients with metabolic disturbances also were observed to have a much poorer prognosis (Hu and Wang, 2021). Additionally, it has been reported that obesity can severely hamper the immune cells responsiveness to weaken the long-term protection against SARS-COV-2 (Stefan et al., 2021). Metabolic disturbances are a common complication of obesity, and only 15%–20% of obese patients are not affected by them (Soverini et al., 2010). Metabolic disturbances have been proven to be a significant aggravating factor in many obesity-related diseases, so the underlying mechanisms linking COVID-19 and metabolic unhealthy obesity (MUO) are need to be better clarified.

Angiotensin Converting Enzyme 2 (ACE2), whose gene expression is found in many human tissues, has been known to play a vital role as a receptor for SARS-CoV-2 entry and infection in target cells (Yan et al., 2020). MUO is a systemic disease, which has been discovered to be associated with the upregulated ACE2 expression in tissues in the whole human body (Zheng et al., 2020). As reviewed by Goossens et al., with the increased number of adipose tissues, the ACE2 expression is upregulated, making the concentration of SARS-COV-2 in adipocytes significantly higher than in other tissue cells, becoming a viral reservoir for SARS-CoV-2 (Goossens et al., 2020). Additionally, the contribution of MUO-related upregulated Transmembrane Serine Protease 2 (TMPRSS2) expression, hyperglycemia, and weakened immune surveillance to the poorer prognosis of COVID-19 in the corresponding patient population are also being in-depth investigated. This serves to demonstrate the potential importance of interaction between MUO and COVID-19.

In this study, we compared transcriptional profiles of COVID-19 with MUO patients. Two datasets were collected from the Gene Expression Omnibus (GEO) database, where GSE196822 (Banerjee et al., 2022) for COVID-19 and GSE152991 (Cifarelli et al., 2020) for MUO. Shared Differentially Expressed Genes (DEGs) were identified through cross-analysis of the two datasets, and the result was used to discover the relevant signaling pathways as well as the genes that are potential therapeutic targets for patients with MUO and COVID-19. Also, efforts to reveal the molecular mechanisms linking MUO and COVID-19 were made, including predictive transcription factor -gene interaction, protein-drug interaction, and gene-disease network analysis based on the identified DEGs. We further determined the association with other diseases that might provide further insights for the study about complications of and treatments for COVID-19. Figure 1 demonstrates the workflow of the entire system biology and bioinformatics analysis. We hope that the findings of this study will provide preliminary information that may help to understand the interaction between COVID-19 and MUO and help in selecting proper drugs and inventing future treatments that can combat COVID-19 and MUO.

MUO is a type of metabolic disorder regarded as the main obesity-related complication. Patients with MUO usually preserve insulin resistance, hypertension, chronic inflammation, and altered liver inflammation, all of which are negative preconditions for the prognosis of COVID-19 infection (Cifarelli et al., 2020). Here, MUO and COVID-19 transcriptomics analysis revealed that 65 shared DEGs show similar expression patterns in these two disorders.

GO pathway analysis was conducted to assess the biological importance of the identified common DEGs in the pathogenesis of MUO and COVID-19. Three types of GO analysis were conducted. Neutrophil-related pathways are among the top GO terms for the biological process, including neutrophil degranulation (GO:0043312), neutrophil activation involved in immune response (GO:0002446) and neutrophil mediated immunity (GO:0002283). Increasing evidence suggests that inhibiting neutrophil degranulation is beneficial for ameliorating inflammation-induced myocyte damage, hepatic acute phase response and thrombosis formation in severe COVID-19 patients (Gutmann et al., 2022). In the molecular function, complement component C3b binding (GO:0001851) and amyloid-beta binding (GO:0001540) are two top GO pathways. Concerning COVID-19, C3b recruits immune cells to the sites of infection and induces activation and further differentiation towards an inflammatory phenotype with the subsequent activation of lectin pathway (LP)-mediated C3b deposition, which is critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 (Ali et al., 2021). Moreover, a previous study found that the raised level of C3b in serum is linked to obesity (Oberbach et al., 2011), which may provide essential insight into the severe inflammation that is occurred in patients with both MUO and COVID-19. In addition, recent research has proved that SARS-CoV-2 infection elevates neuroinflammation by inducing dysregulation of microglia and astrocyte subpopulations, alters brain structure leads to abnormal accumulation of amyloid-beta (Douaud et al., 2022). Similarly, the pathway of activating and modifying proinflammatory cells in the central neuron system (CNS) is also the way that MUO increases the risk of Alzheimer’s disease (Guo et al., 2021). It implicated the underlying synergistic effect of increasing Alzheimer’s disease occurrence on COVID-19 patients with MUO. The top GO terms based on the cellular component were secretory granule membrane (GO:0030667) and tertiary granule (GO:0070820). Besides the neutrophil degranulation, which has been discussed above, the secretory granule is essential for SARS-COV-2 exiting the cell. Intracellular transport of SARS-COV-2 within the cells involves secretory granules, each containing a single virus particle. These vesicles then fuse with the plasma membrane of host cells, releasing the virus outside the cell and facilitating the transmission of SARS-COV-2 (Eymieux et al., 2021). Yeming Yang et al., revealed that metabolic unhealthy disorders could alter the membrane phospholipid distribution in multiple physiological systems (Yang et al., 2021), affecting secretory granule membrane synthesis.

The top pathways terms from the four selected databases were complement and coagulation cascades (KEGG), osteoclast differentiation (KEGG), microglia pathogen phagocytosis (WikiPathways) and inhibition of Matrix Metalloproteinases (MM) (BioCarta). Here, complement and coagulation cascade activation are the common pathways in virus infection and metabolic disorders. COVID-19 induces the pro-inflammatory state, which stimulates uncontrolled activation of the complement system and neutrophil extracellular traps (NETs)-formation, both of which promote the coagulation cascade and induce a state of “thrombo-inflammation” (Borczuk and Yantiss, 2022). In patients with MUO, the dysregulation of secreted proteins and the secretory machinery in the liver lead to the abnormally regulated complement and coagulation cascades (Stocks et al., 2022), suggesting that this cascade can be an important target for developing alternative management measures for patients with both MUO and COVID-19. In addition, recent studies about patients diagnosed with COVID-19 have reported bone loss. Preliminary research showed that it might be due to the SARS-COV-2-induced cytokine dysregulation, as the circulating pro-inflammatory cytokines upregulate osteoclast differentiation in bone tissues (Qiao et al., 2022). Based on that, in MUO patients, the lipid-altering conditions can be aggravated by the altered activity and differentiation of osteoclast, which directly lead to more severe bone loss (Kim et al., 2021). Aside from the skeletal system lesions, the degenerative changes in CNS caused by the neuroinflammation has been identified in SARS-CoV-2 infection patients. It has been believed by some researchers that its underlying pathological pathways can be attributed to microglia pathogen phagocytosis, which is also the key in the sortilin-mediated microglia phagocytes production in obesity patients (Talbot et al., 2018; Ma et al., 2022). After COVID-19 patients were discharged from the hospitals, the pulmonary long-term consequences have been found to depend mainly on the activity of matrix metalloproteinases. The deregulated abnormal accumulation of extracellular matrix protein is crucial in the presence of LONG-COVID symptoms, since that the enzymes are deeply related to tissue repairment (Blanco et al., 2021). As for the obesity patients, the inhibition of matrix metalloproteinases has been proved to suppress glomerular inflammation and fibrogenesis (Niu et al., 2016).

Based on the identified DEGs, a PPI network was constructed to analyze interconnected proteins’ functional characteristics in-depth and predict potential drug targets. The hub genes essential in the pathogenesis of COVID-19 and MUO could be key drug targets and biomarkers in them. The top 10 hub genes associated with COVID-19 and MUO were retrieved through MCC method, including SPI1, CD163, C1QB, SIGLEC1, C1QA, ITGAM, CD14, FCGR1A, VSIG4, C1QC. Protein SPI1 is the essential transcription factor used to predict dysregulated hematopoiesis in bone marrow in severe COVID-19 patients. Recent evidence has proved the link between hematopoietic dysfunction of bone marrow and COVID-19, which is characterized by the accumulation of immature myeloid progenitors and a dramatic reduction of lymphoid progenitors (Wang et al., 2021). Obesity-related abnormal glucose metabolism has also been reported to impair bone marrow function, especially hematopoiesis (Liu et al., 2018). Therefore, patients with MUO precondition are more likely to suffer from severe SARS-COV-2 infection complication. Furthermore, the hub genes C1QA, C1QB, C1QC, VSIG4 and CD14 have been regarded as the main biomarkers for predicting macrophage and neutrophil mediated inflammation, especially in the respiratory and cardiovascular systems (Zhang and Zhang, 2022). They are also the essential biomarkers that have been identified in the unfavorable metabolic profile of MUO patients (Chang et al., 2019). Additionally, during the recovery process of patients, especially in the early recovery stage (ERS), the ratio of classical CD14⁺ monocytes was reported to be elevated, accompanied by high expression of inflammatory genes, which prevented patients from achieving a better prognosis. The hub protein ITGAM is an essential molecular receptor that plays a vital role in many complements mediated pathways that aggravate the COVID-19 symptoms, such as the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome (Carvelli et al., 2020). It is also a critical marker for inflammatory macrophages, whose infiltration can be elevated due to obesity (Moreno-Indias et al., 2016). Bronchoalveolar lavage fluid CD4⁺ T cells of patients with COVID-19 were T_H1-skewed and showed de-repression of genes downregulated by Vitamin D which notably activates the recruiting of c-JUN and switches on the pro-inflammatory programs of T_H1 cells (Chauss et al., 2022). This c-JUN mediated cascade has also been discovered to be activated by increased metabolic stress caused by obesity (Wang et al., 2020). Based on this information, we can speculate that the induced raised degree of macrophage infiltration and transcriptional factors activation by glucose metabolism and oxidative phosphorylation can lead to a poorer prognosis and higher mortality of COVID-19.

TFs mainly regulated transcription and expression of target genes. This result revealed transcription factors regulator network in the COVID-19 and MUO, including FOXC1, GATA2, YY1, DHRS9, NFIC, CREB1, JUN, TMC5, HINFP, and FOXL1. In previous bioinformatics analysis, several separate studies revealed that some essential TFs, including FOXC1, GATA2, YY1 and FOXL1, are associated with SARS-CoV-2 infection (Islam et al., 2020; Auwul et al., 2021; Ahmed et al., 2022; Lu et al., 2022; Hossain et al., 2023). GATA2 is associated with hematopoietic and immune deficiency of COVID-19 (Collin et al., 2015). JUN is a subunit of activating protein 1, an inducible transcription factor composed of multiple protein complexes, that plays a role in several types of cell differentiation and inflammation (Chang et al., 2013). Moreover, CASP1 is the most involved pathway in cytokine storm, and YY1 is a crucial TF in CASP1 expression (Zheng et al., 2022). In obese mouse models, YY1 was markedly upregulated (Lu et al., 2014), which may provide us with the possible cause of increased mortality in COVID-19 patients with MUO.

Several drugs have been extracted as candidate treatments against COVID-19 and MUO. We discovered 3,3′,4,4′,5-Pentachlorobiphenyl, a compound that inhibits or antagonizes the action or biosynthesis of estrogenic compounds, as the candidate drug for treating COVID-19. This may reason for the observed moderate decrease of pulmonary ACE2 expression after administration of the androgen receptor antagonist enzalutamide, which is documented in recent studies (Lott et al., 2022). This effect may play a positive role in reducing the incidence of respiratory complications in patients with MUO. Another extracted drug was PD 98059, which is applied for the inhibition of MAP-kinase (MAPK) kinase activation. The MAPK pathway is one of the most involved pathways causing cytokine storm in patients with severe COVID-19 (COvid-19 Multi-omics Blood ATlas COMBAT ConsortiumCOvid-19 Multi-omics Blood ATlas COMBAT Consortium, 2022; Geng et al., 2021). The inhibition of this pathway is a promising therapeutic target for preventing severe COVID-19. PD 98059 can relieve obesity induced by high fat diet (Zheng et al., 2023). Moreover, this study found medroxyprogesterone acetate, dexamethasone and tretinoin as potential drugs. Medroxyprogesterone acetate, a progestin, was recently tested as a drug for HIV patients (Vanpouille et al., 2021). Several clinical trials have been carried out to study dexamethasone’s therapeutic effect on COVID-19 infection. Many results have proved that it can regulate inflammation-mediated lung injury (Horby et al., 2021), thereby reducing the progress of respiratory failure and death; at the same time, attention has been paid to its positive effect on neutrophil aggregation and interferon system imbalance caused by COVID-19 (Sinha et al., 2022). Moreover, as has been shown by drug tests in human cell lines and human lower respiratory organoids, tretinoin, as a derivative of vitamin A, has antiviral activity against all SARS-COV-2 antibodies (Tong et al., 2022). Several studies have indicated that carotenoids and carotenoid conversion products with provitamin A activity have anti-obesity activity (Gomes et al., 2021).

The gene-disease analysis was performed to predict relationships between common DEGs and different disorders. The analysis showed various diseases correlated with MUO and COVID-19, including liver, immune and cardiovascular system disorders. Liver cirrhosis has also been found in our gene-disease network; the patients with it have a higher probability of severe COVID-19 symptom, particularly high rates of hepatic decompensation and death (Marjot et al., 2021). Furthermore, COVID-19 infection and MUO have been shown to cause and aggravate various chronic liver diseases (Steenblock et al., 2021; Kouvari et al., 2022). The immune system diseases also showed a strong correlation in the gene-disease network. IGA Glomerulonephritis is a kind of immunoglobulin A related inflammation and usually occurs following viral infection. Increasing evidence supports that COVID-19 infection and vaccination against SARS-CoV-2 may trigger or exacerbate IGA Glomerulonephritis (Bronz et al., 2022). Another strongly correlated immune disease identified in the network is Lupus Erythematosus, Systemic. During the COVID-19 pandemic, patients with Lupus Erythematosus, Systemic have lowered risk of COVID-19, hospitalized COVID-19 or severe COVID-19 (Ran et al., 2022), suggesting that this specific precondition blocks the entry of the virus and transmission in some way. Moreover, the involvement of myocardial ischemia in COVID-19 is directly associated with cytokine-mediated plaque destabilization and hypercoagulability, which induce ischemic stroke and acute myocardial infarction (Modin et al., 2020). Additionally, there is a significant correlation between metabolic disorders and prolonged QTc interval, which is the early marker of transient myocardial ischemia (Guo et al., 2017).

In addition to presenting some interesting findings, our study has some limitations. These results, including DEGs and candidate drug identification, as well as all the network analysis, were obtained by bioinformatics and system biology approach. The results need further experimental verification. Additionally, the selected datasets include different groups of people with two different diseases, rather than the same population with both MUO and COVID-19. Thus, further studies and clinical trials are needed to validate the biological functions of the identified hub genes and the safety and efficacy of the specified candidate drugs, as well as their pharmacological characteristics.