Abstract: Objective To explore the effect of TRAF-interacting protein with FHA domaincontaining protein A(TIFA)on pyroptosis of renal tubular epithelial cells and examine whether or not it operates through NF-κB signaling pathway. Methods Blood specimens were collected from 12 septic patients with acute kidney injury(AKI)in intensive care unit(ICU). The levels of creatinine and TIFA were measured. The expressions of TIFA,caspase-1 and GSDMD were detected by Western blot and mitochondrial membrane potential by JC-1. Septic model was established by cecal ligation and puncture and the mice received an intraperitoneal injection of TLR4 inhibitor for detecting renal injury and the expression of TIFA. Results Urinary TIFA rose after renal injury in septic patients. In renal tubular epithelial cells,a knockdown of TIFA could suppress the expressions of Caspase-1 and GSDMD and minimize the change of mitochondrial membrane potential. In septic AKI mice,an inhibition of TLR4 signaling pathway could suppress TIFA and NF-κB,reduce the production of inflammatory cytokines IL-1β and IL-18 and improve renal pathology and survival rate. Conclusion TIFA may reduce pyroptosis by inhibiting NF-κB signaling pathway in septic AKI. Targeted treatment of TIFA may improve septic AKI.