Hederasaponin C inhibits LPS‐induced acute kidney injury in mice by targeting TLR4 and regulating the PIP2/NF‐κB/NLRP3 signaling pathway

Abstract Acute kidney injury (AKI) is a common clinical condition associated with increased incidence and mortality rates. Hederasaponin C (HSC) is one of the main active components of Pulsatilla chinensis (Bunge) Regel. HSC possesses various pharmacological activities, including anti‐inflammatory activity. However, the protective effect of HSC against lipopolysaccharide (LPS)‐induced AKI in mice remains unclear. Therefore, we investigated the protective effect of HSC against LPS‐induced renal inflammation and the underlying molecular mechanisms. Herein, using MTT and LDH assays to assess both cell viability and LDH activity; using dual staining techniques to identify different cell death patterns; conducting immunoblotting, QRT‐PCR, and immunofluorescence analyses to evaluate levels of protein and mRNA expression; employing immunoblotting, molecular docking, SPR experiments, and CETSA to investigate the interaction between HSC and TLR4; and studying the anti‐inflammatory effects of HSC in the LPS‐induced AKI. The results indicate that HSC inhibits the expression of TLR4 and the activation of NF‐κB and PIP2 signaling pathways, while simultaneously suppressing the activation of the NLRP3 inflammasome. In animal models, HSC ameliorated LPS‐induced AKI and diminished inflammatory response and the level of renal injury markers. These findings suggest that HSC has potential as a therapeutic agent to mitigate sepsis‐related AKI.