[Letter]GSK-LSD1, an LSD1 inhibitor, quashes SARS-CoV-2-triggered cytokine release syndrome in-vitro
Authors and Affiliations
Since the COVID-19 demonstrated a remarkable transmission speed and a high mortality risk, COVID-19 is currently declared as a pandemic by the World Health Organization. This is the first time that the WHO has declared a pandemic since H1N1 in 2009. As of 6 September 2020, the total number of COVID-19 patients is 26,763,217 (876,616 deaths), and it continues to rise (https://covid19.who.int/). In spite of the urgent demand for the vaccines and therapeutics, global efforts are primarily focused on the utilization of the existing anti-viral drugs, such as remdesivir, hydroxychloroquine, and dexamethasone, to relieve the symptoms due to the limited development of renovative therapeutics. Therefore, more fundamental solutions are urgently needed to overcome the threat of the COVID-19. The deterioration of the COVID-19 patients with acute respiratory distress syndrome (ARDS) and sepsis are mainly caused by the cytokine storm, the overproduced cytokines by immune cells. Previous studies indicated that the infection does cause the cytokine storm and subsequently ARDS, and may lead to mortality.1 Therefore, the suppression of the cytokines and subsequent ARDS is important to increase survival rate through the regulation of cytokine gene expression.2 Although NF-κB signaling is known to regulate the cytokine storm, direct targeting of NF-κB is not beneficial since the p65 is readily hyperactivated in COVID-19 patients. Here, we applied a mechanism by which previously reported phosphorylated lysine-specific demethylase 1 (LSD1) stabilizes NF-κB p65 to control the expression of pro-inflammatory cytokine genes.3 We found that pro-inflammatory cytokines were significantly reduced when severe COVID-19 patients’ peripheral blood mononuclear cells (PBMCs) were treated in-vitro with Go6976 (inhibitor of LSD1 phosphorylation) or GSK-LSD1 (inhibitor of LSD1 activity). Therefore, this study suggests the GSK-LSD1 as a therapeutic agent for severe COVID-19 patients that are difficult to treat by directly targeting NF-κB.