Sepsis is a common life-threatening pathology. This study investigated the role of transcription factor sex-determining region Y (SRY)-box 9 (SOX9) in sepsis-induced cardiomyocyte pyroptosis. A murine model of sepsis was established, followed by detection of cardiac functions and myocardial injury. HL-1 mouse cardiomyocytes were induced by lipopolysaccharides (LPS). The levels of interleukin (IL)-18, IL-1β, tumor necrosis factor-α (TNF-α), IL-6, malondialdehyde (MDA), and superoxide dismutase (SOD) in myocardial tissues and HL-1 mouse cardiomyocytes were determined. SOX9 ubiquitination level was measured. The binding relationships between SOX9-miR-96-5p and miR-96-5p-NLR pyrin domain containing 3 (NLRP3) were analyzed, and the interaction between ubiquitin-specific peptidase 7 (USP7) and SOX9 was measured. SOX9 was highly expressed in septic mice and LPS-induced HL-1 mouse cardiomyocytes. SOX9 silencing improved cardiac function, alleviated myocardial injury, reduced the levels of IL-1β, IL-18, cleaved caspase-1, gasdermin D N-terminal domain, TNF-α, IL-6, and MDA in myocardial tissues and HL-1 mouse cardiomyocytes, increased the level of SOD, and alleviated cardiomyocyte pyroptosis. USP7 upregulated SOX9 expression through deubiquitination. SOX9 inhibited miR-96-5p expression and miR-96-5p targeted NLRP3. miR-96-5p silencing or USP7 overexpression reversed the inhibitory effect of SOX9 silencing on cardiomyocyte pyroptosis. Collectively, USP7 upregulated SOX9 expression through deubiquitination, and SOX9 suppressed miR-96-5p expression by binding to the miR-96-5p promoter region, thereby promoting NLRP3 expression and then exacerbating sepsis-induced myocardial injury and cardiomyocyte pyroptosis.
Keywords: SOX9; USP7; myocardial injury; pyroptosis; sepsis; ubiquitination.