Luteolin is a natural flavonoid compound with multifaceted pharmacological properties, including anti-oxidant, anti-inflammatory, antiviral, and anti-tumor activities. Network pharmacology analysis has been utilized to decipher the underlying mechanisms and multitargets of luteolin against coronavirus disease 2019 (COVID-19). This review aims to provide a systematic and comprehensive summary of luteolin, as a potential novel remedy with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity, as well as its anti-oxidant mechanisms. We systematically delineate the epidemiological profile, genomic architecture, and replicative dynamics of SARS-CoV-2, thereby constructing a multiscale framework to decode its pathogenic mechanisms. Employing a multi-level network pharmacology analytical strategy, we identify 46 core targets through protein interaction network construction, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Molecular investigations reveal luteolin’s dual antiviral mechanisms, including direct targeting of SARS-CoV-2 proteins and host-directed intervention through suppression of angiotensin-converting enzyme 2 receptor engagement/transmembrane protease serine 2-mediated viral priming. The polypharmacological profile of luteolin demonstrates synergistic effects in blocking viral entry, replication, and host inflammatory cascades. This phytochemical repurposing study of luteolin provides a novel mechanistic paradigm for developing multitarget antiviral agents, highlighting the translational value of natural compounds in combating emerging viral variants.

The high infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stems from the insertion of four distinct amino acid residues (RRAR), called polybasic cleavage site in the spike (S) protein, that is strikingly identical with that of epithelial sodium channel (ENaC), both of which can be cleaved by plasmin. Dysregulation of human ENaC, a protein responsible for regulating fluid balance, is directly associated with mortality resulting from pulmonary damage, whereas the involvement of ENaC and regulation by fibrinolytic system during SARS-CoV-2 infection remains elusive. In this study, S plasmid and pseudovirus were applied to mimic SARS-CoV-2 infection, respectively. Pulmonary edema manifestations and dysregulation of ENaC were observed in mice expressing human angiotensin converting enzyme 2, and mechanistic studies revealed both S protein and ENaC could be cleaved by plasmin. Furthermore, our results demonstrated that S protein competitively inhibited the cleavage of ENaC by plasmin, overexpression of ENaC suppressed plasmin-induced cleavage of the S protein, thereby impeding SARS-CoV-2 invasion. Notably, co-enabling the polybasic cleavage site mutated S plasmid/pseudovirus with plasmin reversed the downregulation of ENaC. In conclusion, our data suggest a competitive mechanism of ENaC by SARS-CoV-2 via plasmin was mainly regulated at polybasic cleavage site, indicating a novel mechanism underlying SARS-CoV-2-induced pulmonary edema, and identifying ENaC as a potential therapeutic target for treating SARS-CoV-2-associated respiratory failure.

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), remain critical clinical challenges characterized by acute diffuse lung inflammation, alveolar-capillary barrier disruption, and refractory pulmonary edema, leading to high morbidity and mortality. The alveolar epithelium, a key structural and functional unit of the lung, plays a pivotal role in maintaining alveolar fluid homeostasis, which depends on coordinated transcellular ion transport and paracellular barrier integrity mediated primarily by the epithelial sodium channel (ENaC) and tight junction proteins. As a central regulator of alveolar fluid clearance, ENaC mediates sodium ion reabsorption across the alveolar epithelium, whereas tight junction proteins, including zonula occludens-1, occludin, and claudins, restrict paracellular leakage and maintain epithelial barrier integrity. In the pathological setting of ALI/ARDS, both ENaC and tight junction proteins undergo significant dysregulation, with reduced ENaC function leading to impaired alveolar fluid clearance and exacerbated edema, while alterations in the expression, distribution, and function of tight junction proteins further compromise barrier integrity. Despite their individual roles being increasingly recognized, the complex interplay between ENaC and tight junctions in the alveolar fluid homeostasis of ALI/ARDS, as well as the underlying regulatory mechanisms, remain incompletely understood. This review therefore focuses on the mechanistic and functional crosstalk between ENaC and tight junction proteins, integrating their coordinated roles in alveolar fluid transport, barrier dysfunction, and pulmonary edema, and discussing potential therapeutic strategies with this coupled regulatory system in ALI/ARDS.