Decoding the Role of NF-κB Signaling in COVID-19 Severity and Inflammation

BACKGROUND Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with an overactive immune response, contributing to disease severity. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway plays a central role in mediating inflammatory responses during viral infections, including COVID-19. OBJECTIVES This computational reanalysis explores the critical involvement of NF-κB signaling, particularly through toll-like receptor (TLR) activation and noncanonical pathways, in SARS-CoV-2 cellular entry, immune activation, and cytokine storm. We also discuss the crosstalk between NF-κB and other signaling pathways in the context of COVID-19, and summarize current and potential therapeutic strategies targeting NF-κB. METHODS An extensive literature review was conducted using databases such as PubMed, Scopus, and Web of Science. Studies focusing on SARS-CoV-2 entry mechanisms, TLR signaling, NF-κB pathway activation, noncanonical NF-κB signaling, and anti-inflammatory drug interventions were analyzed and synthesized. RESULTS SARS-CoV-2 enters host cells via angiotensin-converting enzyme 2 receptors, often facilitated by transmembrane protease serine 2 protease activity. This viral entry triggers downstream immune signaling cascades, especially through TLR3, TLR4, and TLR7/8. TLR engagement activates both canonical and noncanonical NF-κB pathways, leading to the expression of pro-inflammatory cytokines such as interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta. NF-κB signaling exhibits extensive crosstalk with other pathways, including Janus kinase/signal transducer and activator of transcription and NOD-like receptor protein 3 inflammasome (NLRP3) activation, contributing to cytokine storm and lung injury. Several pharmacological agents, including corticosteroids, Inhibitor of κB Kinase ( IKK) inhibitors, and repurposed drugs like dexamethasone and resveratrol, show potential in mitigating NF-κB-mediated inflammation. CONCLUSION NF-κB signaling serves as a pivotal mediator of SARS-CoV-2-induced inflammation and immune dysregulation. Targeting this pathway—particularly its noncanonical branches and TLR-mediated activation—offers promising therapeutic avenues. Understanding NF-κB crosstalk with other immune pathways may yield synergistic drug targets to improve COVID-19 outcomes.