Taken together, the findings of the present highlight the role of SARS-CoV-2 S protein as an ethiopatogenic agent in the clinical manifestations in acute or long COVID-19 and raises opportunities for novel pharmacological interventions based on S protein blockade, NLRP3 inhibition, monoclonal antibodies or fusion proteins against IL-1β or IL-1R and TLR4 antagonists, among other, together with anticoagulant therapies. Here, TLR4 is linked to COVID-19.