The global outbreak of COVID-19 can be attributed to the emergence of the SARS-CoV-2 virus, and has caused unprecedented health consequences across the world (1). SARS-CoV-2 infection occurs through exposure to respiratory aerosols and droplets (2–4). The virus is capable of inducing direct endothelial injury, thrombo-inflammation, immune system dysregulation, and changes in ACE2-associated pathways (5–8). Severe COVID-19 is typically characterized by pulmonary infection accompanied with cough, fever and dyspnoea (9). The most severe pathophysiologic symptoms of COVID-19 include the damage of pulmonary epithelia, hypercoagulation, thrombosis and excessive vascular permeability resulting into sepsis (10).

Preeclampsia, an ailment associated with pregnancy that commonly presents around the 20-week gestation mark, and is symptomized by placental oxidative stress, endothelial damage and antiangiogenesis that induce proteinuria, hypertension, and similar multiorgan responses as observed in severe COVID-19 cases (11–14). It has been reported in recent studies that there is a strong connection of COVID-19 with preeclampsia in pregnant patients (15, 16). The infection caused by SARS-CoV-2 during pregnancies can induce risks for both the mother and the developing fetus, contributing to pregnancy-related complications like preeclampsia and impaired intrauterine growth (17–26). Several studies have indicated an elevated likelihood of perinatal outcomes in pregnant individuals with COVID-19, including more proneness to preeclampsia and premature parturition (27). It is thus important to assess the impact of COVID-19 on the preeclampsia patients, and identify potential therapeutic interventions to lower the likelihood of hospitalization or mortality.

Through the analysis of blood RNA sequencing data from individuals with COVID-19 and preeclampsia, this study reveals shared DEGs. Moreover, to validate our bioinformatics findings, we performed experimental validation using PBMC samples obtained from healthy individuals, COVID-19 patients, and preeclampsia patients. Our findings further reinforce the potential of the identified molecules in serving as therapeutic targets for both COVID-19 and preeclampsia, providing valuable insights for the development of effective treatments.

It has been demonstrated by more and more recent studies that plausible associations could exist between distinct medical conditions. Identification of these associations can be a promising step for future disease studies (43–45). Public health systems are facing unprecedented challenges due to the COVID-19 pandemic. In spite of being primarily deemed as a respiratory complication, infection with SARS-CoV-2 has the potential to influence on endothelial cells, resulting into microvascular dysfunction, microthrombosis and endotheliitis (46). It has been shown recently that preeclampsia patients are more prone to SARS-CoV-2 infection and high COVID-19 mortality than healthy populations (18, 47–49). Instead of immunosuppression observed during normal pregnancies, preeclampsia patients shows aberrant and excessive activation of immune system, characterized by an upregulation of antiangiogenic factors and proinflammatory cytokines in both the maternal endothelia and intrauterine environment, inducing placental insufficiency and systemic complication (50, 51). However, it is still unclear what molecular mechanism contributes to a worse COVID-19 prognosis among preeclampsia patients. Inspired by the finding of possible correlation of Coronavirus infection and an increased risk of preeclampsia during gestation, we investigated the possible connections between preeclampsia and COVID-19 at the transcriptomic level. A network-centric strategy was utilized for analyzing the RNA-seq profiling datasets for both preeclampsia and COVID-19, and for identifying the potential diagnostic biomarkers for preeclampsia among COVID-19 pregnancies.

MRPL11 is a coding gene, and has connection with diseases such as Dyskinetic Cerebral Palsy (52). MRPS12 is located cytogenetically on 19q13.2, and responsible for encoding a 28S ribosomal subunit of S12P family. It has been reported in previous studies that MRPS12 is a critical component of small ribosomal subunits, and regulates the fidelity of decoding and the vulnerability to aminoglycosidic antibiotics (53, 54). An upregulation of MRPS12 is observed in different types of cancer as opposed to non-tumor controls (55). UQCRH is a vital element of the multisubunit transmembrane complex within the mitochondrial electron transport chain, facilitating the movement of electrons from cytochrome c to c1 (56). UQCRH can serve as an indicative marker for assessing the prognosis of liver cancer. Alteration in mitochondrial respiration could be conducive to tumorigenic processes through aberrant biological stress, such as reactive oxygen species (57). ATP5I assists in forming the structure of ATP-generating enzyme, correlating with oxidative phosphorylation in the mitochondria (58). UQCRQ mutation can lead to deficiency of mitochondrial complex III, inducing neurodegeneration characterized by psychomotor retardation or encephalopathy (59, 60). ATP5D is a subunit of ATP synthase, and its knockdown can lead to reduction in the ATP synthase level (61–63). COX6B1 is a subunit of COX complex, and is present in various types of cells, such as HeLa cells and yeast (64). In addition, recent research has reported that COX6B1 dysregulation could have significant effect on the COX functions, possibly resulting into the development of hydrocephalus, cerebromyopathy and other disorders (65, 66). The ATP5O expression has been reported to play critical roles in diagnosing and prognosing gastric cancer, and the analysis based on NextBio database reveals a downregulation of ATP5O expression in ccRCC (67, 68). ATP5H serves as an essential part of mitochondria responsible for energy production in eukaryotes; therefore, it is reasonable to expect dysregulation of ATP synthase expression in cancer cells would affect tumoral metabolism (69). The NDUFA6 protein is a subunit of NADH dehydrogenase (ubiquinone), the largest of five electron transport chain complexes localized within the internal membrane of mitochondria.

It has been reported that binding between the SARS-CoV-2 and ACE2 receptor could reduce the angiotensin 1-7 level, and induce vasoconstrictive, pro-inflammatory, and pro-coagulant effects, potentially resulting into vascular lesions in the placenta and preeclampsia (46, 70–72). Based on these data, it is of urgent need to perform mechanistic studies to better understand the infection of COVID-19 associated with preeclampsia. GO and KEGG analysis was performed in this study for identifying the connection between preeclampsia and COVID-19. clusterProfiler was used for GO analysis of BPs, CCs, and MFs. The MFs for these common DEGs primarily showed enrichment in the mitochondrial protein-containing complexes, inner membranes of mitochondria, and mitochondrial inner membrane protein complexes. The pathological and biochemical effects induced by COVID-19 could result into an acute inflammatory state (73). Such inflammatory conditions might have associations with hypermetabolic status, e.g., hyperglycemia, and with cellular dysregulation, e.g., mitochondrial dysfunction, considering their involvement in cellular functions and metabolic pathways (74, 75). Therefore, it is essential to analyze the roles played by cellular apparatus and molecules that have direct links with oxidative-stress regulations (73, 76). Identification of significant GO and molecular pathways could help us better understand the mechanism by which preeclampsia increases the COVID-19 mortality rate.

The links between TFs, miRNA, and common DEGs were then investigated. TFs are critical cellular expression-controlling factors. The activities of TFs dictate the cellular functions and responses to environments (77). TFs are also critical cancer-cell stemness enablers, providing support for maintenance and functions of cancer stem cells which are deemed as sources for tumoral development and metastasis, as well as drug resistance (78). In this study, ILF3, HTT, AR, MYC, RARA, IRF4, RAD21, JUN, SREBF1, and JUND were ranked and identified as the top 10 TFs based on the P-values. miRNAs could serve as both tumor suppressors and oncogenes depending on cellular conditions. miRNA could function as a down-regulator of mRNAs by competitively forming base-pairs with them (79). miRNA dysregulation has been reported to affect cancer phenotypes, including proliferative signaling activation, growth suppression evasion, apoptosis suppression, enhanced cellular invasion and metastasis, and increase of angiogenic activities (80). Hsa-miR-126-3p, hsa-miR-32-3p, hsa-miR-192-5p, hsa-miR-215-5p, hsa-miR-380-3p, hsa-miR-9-3p, hsa-miR-4666a-3p, hsa-miR-381-3p, hsa-miR-34a-5p, and hsa-miR-5692b were among the ten most significant miRNAs.

Furthermore, gene-disease relationship analysis was performed for the identification of common DEGs linked to diseases. It was revealed by the analysis that common DEGs are associated with various types of diseases including HIV and COVID-19, including Renal fibrosis, Ureteral obstruction, Colonic Neoplasms, Idiopathic Nephrotic Syndrome, IGA Glomerulonephritis, Burkitt Lymphoma, Medullary Neoplasms, Neuroblastoma, Congenital aneurysm of ascending aorta, and Mitochondrial Diseases. It has been suggested by recent studies that COVID-19 patients with cancer are more likely to develop severe symptoms and even suffer high mortality than non-cancer patients (81–86). COVID-19 is also shown to have a significant connection with neoplasms, such as gastrointestinal, colonic and prostatic neoplasm (83, 87, 88). These results are in consistency with our finding. More and more evidences suggest worse clinical outcomes in cancer patients with COVID-19 as opposed to non-cancer patients (89–93).

It is a high priority to develop effective and safe drugs for preeclampsia-affected COVID-19 patients. Multiple molecules and drugs have been identified in this study that might have therapeutic potential for COVID-19 patients affected with preeclampsia, including valproic acid, verteporfin, 7646-79-9, astemizole, vinblastine, colchicine, doxorubicin, ambroxol, phenobarbital, and copper sulfate. Valproic acid as well as its amidic derivatives (valnoctamide and valpromide) have long been demonstrated as an effective antiviral by inhibiting in vitro infection of a wide range of viruses (94, 95). Valproic acid may decrease the SARS-CoV-2 viral load, thus reducing infection risk by targeting the ACE2 receptor and transmembrane serine protease 2 (96). Verteporfin and protoporphyrin IX (PpIX), both approved by FDA, could inhibit the SARS-CoV-2-induced cytopathic effects, both at a low EC50 level (nanomolar) (97). Astemizole could also suppress the invasion of SARS-COV-2 Spike pseudovirus by binding with its ACE2 receptor (98). Colchicine can induce anti-inflammatory effects, and thus contribute to the mitigation of cytokine storm by acting on NLRP3 and inhibiting activities of IL-1β, IL-6, and IL-18 (99). Doxorubicin has reported efficacy against viral proteases in SARS-CoV-2 (100), while Ambroxol, known for its mucolytic effects in treating respiratory disorders, may show promise against SARS-CoV-2 by inducing autophagy (101).

Our study presents certain limitations. Firstly, while we identified potential drugs, the absence of clear targets necessitates further in-depth exploration into their specific mechanisms in future research. Secondly, our data did not include patients simultaneously affected by both COVID-19 and preeclampsia. Analyzing data with such dual conditions holds substantial implications. This analysis facilitates the identification of shared genetic features and molecular mechanisms between preeclampsia and COVID-19, shedding light on their underlying connections. Moreover, the discovery of common gene expression changes in both diseases opens avenues for potential novel biomarkers, contributing to the development of diagnostic or prognostic indicators. As pandemic restrictions ease, the increasing opportunities to collect specimens with these coexisting conditions will fuel continued in-depth research in the future.

In summary, our study may provide a new line of research in identifying the crosstalk between COVID-19 and Preeclampsia. First, we used GEO databases to identify hub genes which could contribute to the occurrence and development of COVID-19 and preeclampsia. Secondly, the interactions between CVOID-19 and preeclampsia were identified, thus shedding novel light on the molecular mechanisms that underlie the COVID-19 infection and preeclampsia. Finally, ten candidate drugs, which could potentially act as therapeutic biomarkers for COVID-19 and preeclampsia, were identified.

In summary, this study uncovered shared molecular pathways and hub genes between COVID-19 and preeclampsia. The identified hub genes (MRPL11, MRPS12, UQCRH, ATP5I, UQCRQ, ATP5D, COX6B1, ATP5O, ATP5H, NDUFA6) exhibited distinct expression patterns validated through RT-qPCR. The findings provide crucial insights for potential therapeutic targets and further understanding of the molecular interplay between these conditions.

The original codes used for the analyses presented in the study are publicly available. This data can be found here: https://github.com/Liujunxiu97/Covid19-and-Preeclampsia.

The studies involving humans were approved by the affiliated hospital of Qingdao university. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. The participants gave their consent to publish the study.

YC, LX, and ML designed the project. YC, JW, MS and WX developed the experiments. YC, and LX analyzed the data. YC and LX wrote the paper. All authors contributed to the article and approved the submitted version.