Abstract
COVID-19 pathophysiology is caused by a cascade of respiratory and multiorgan failures arising, at least in part, from the SARS-CoV-2-driven dysregulation of the master transcriptional factor STAT3. Pharmacological correction of STAT3 over-stimulation, which is at the root of acute respiratory distress syndrome (ARDS) and coagulopathy/thrombosis events, should be considered for treatment of severe COVID-19. In this perspective, we first review the current body of knowledge on the role of STAT3 in the pathogenesis of severe COVID-19. We then exemplify the potential clinical value of treating COVID-19 disease with STAT3 inhibitors by presenting the outcomes of two hospitalized patients with active cancer and COVID-19 receiving oral Legalon®—a nutraceutical containing the naturally occurring STAT3 inhibitor silibinin. Both patients, which were recruited to the clinical trial SIL-COVID19 (EudraCT number: 2020-001794-77) had SARS-CoV-2 bilateral interstitial pneumonia and a high COVID-GRAM score, and showed systemic proinflammatory responses in terms of lymphocytopenia and hypoalbuminemia. Both patients were predicted to be at high risk of critical COVID-19 illness in terms of intensive care unit admission, invasive ventilation, or death. In addition to physician’s choice of best available therapy or supportive care, patients received 1050 mg/day Legalon® for 10 days without side-effects. Silibinin-treated cancer/COVID-19+ patients required only minimal oxygen support (2–4 L/min) during the episode, exhibited a sharp decline of the STAT3-regulated C-reactive protein, and demonstrated complete resolution of the pulmonary lesions. These findings might inspire future research to advance our knowledge and improve silibinin-based clinical interventions aimed to target STAT3-driven COVID-19 pathophysiology.
Highlights
Aberrant transcriptional rewiring towards STAT3 has emerged as the master effector/mediator of all the different types of the signaling nodes in type 2 alveolar cells, macrophages, extracellular matrix, T-lymphocytes, and blood, triggering the majority of symptoms observed in hospitalized patients with COVID-19, including proinflammatory conditions, profibrotic status, T-cell lymphopenia, and rapid coagulopathy/thrombosis [13] (Figure 2)
STAT3-plasminogen activator inhibitor-1 (PAI-1) interactome in multiple cellular compartments drives a catastrophic cascade of life-threatening systemic events of inflammation, fibrosis, and coagulopathy/thrombosis characteristics seen in severe cases of COVID-19
We present the outcomes of two hospitalized patients with active cancer and COVID19 receiving Legalon® (Figure 5)
Summary
During SARS-CoV-2 infection, several viral proteins antagonize the IFN-I production pathway and the downstream activation of JAK (Janus kinase)-STAT1 signaling. Pharmaceuticals 2022, 15, 19 amplification cascade via cis and trans-presentation signaling in inflammatory immune cells as well as trans signaling in nonimmune cell compartments such as endothelial cells, overall contributing to key pathophysiologic phenotypes, including ARDS and thrombosignaling in nonimmune cell compartments such as endothelial cells, overall contributing embolic events. Aberrant transcriptional rewiring towards STAT3 has emerged as the master effector/mediator of all the different (cis and trans-presentation) types of the signaling nodes in type 2 alveolar cells, macrophages, extracellular matrix, T-lymphocytes, and blood, triggering the majority of symptoms observed in hospitalized patients with COVID-19, including proinflammatory conditions, profibrotic status, T-cell lymphopenia, and rapid coagulopathy/thrombosis [13] (Figure 2). The escalating activation of the STAT3-PAI-1 interactome in multiple cellular compartments drives a catastrophic cascade of life-threatening systemic events of inflammation, fibrosis, and coagulopathy/thrombosis characteristics seen in severe cases of COVID-19
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