Pleiotropic Role of TNIK in Sepsis‐Induced Cardiomyopathy

ABSTRACT Heart failure induced by sepsis is considered one of the foremost contributors to mortality in intensive care unit (ICU) patients. However, the molecular mechanism of myocardial damage in sepsis has not been fully elucidated at present. TNF receptor‐associated factor‐2 and Nck‐interacting protein kinase (TNIK) are members of the germinal center kinase superfamily. TNIK exhibits a pivotal role as a conserved modulator of glucose and lipid homeostasis. Here, we aimed to investigate the potential direct roles of TNIK and whether TNIK exerts anti‐septic myocardial damage by regulating the NLRP3 pathway. We initially revealed that TNIK was the crucial involvement of septic myocardial injury. Subsequently, we constructed a cecal ligation and puncture (CLP) mouse model and employed LPS‐induced injury in HL‐1 cardiomyocytes. Our observations revealed an upregulation of TNIK levels in both CLP‐injured mice and LPS‐treated HL‐1 cells. However, TNIK inhibitor TNIK‐IN‐7 or siRNA attenuated cardiomyocyte LPS injury. Especially, TNIK siRNA can significantly downregulate TNIK as well as decrease NLRP3 and IL‐1β mRNA and protein levels, though the explicit molecular mechanisms of TNIK‐NLRP3 in septic myocardial require further investigation. Together, our investigation presents novel evidence suggesting TNIK as a potential therapeutic target for the prevention and therapeutic intervention in sepsis‐induced cardiomyopathy.