Fig. 3

Cytokine storm: Molecular mechanism and potential therapeutics in COVID-19. Lung infection by SARS-CoV-2 leads to production of several pro-inflammatory cytokines by innate immune cells. The combination of tumor necrosis factor (TNF) and interferon (IFN)-γ activates PANoptosis leading to a cytokine storm loop, which further potentiates cytokine release and perpetuates PANoptosis. This positive feedback loop can result in systemic inflammation, multiorgan failure, and lethality. Synergism of TNF and IFN-γ activates signal transducer and activator of transcription 1 (STAT1) signaling and induces expression of IFN regulatory factor 1 (IRF1), which regulates inducible nitric oxide synthase (iNOS) for nitric oxide (NO) production. This pathway leads to the induction of PANoptosis, which is regulated through a multiprotein complex called the PANoptosome. Based on the molecular mechanisms engaged by TNF and IFN-γ for the activation of PANoptosis, several drugs can potentially be repurposed for COVID-19 treatment