Liquiritigenin regulates MAPK (p38/JNK) signaling through inhibition of IRAK4, attenuates inflammatory response, fibrosis and kidney dysfunction in a high-salt diet induced chronic kidney disease.

High salt diet (HSD) has adverse effects on the kidneys and causes chronic kidney disease (CKD), leading to kidney dysfunction, usually accompanied by an inflammatory response and fibrosis. In the present study, an in vivo model of renal injury on a high-salt diet was established and its protective effects were assessed by gavage of liquiritigenin (20, 40 and 60 mg/kg) in CKD male BALB/c mice. An in vitro model of NaCl (80 mM) stimulated HK-2 cells and the underlying the mechanism was investigated thoroughly overexpressing Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) to validate the target of liquiritigenin under therapeutic conditions. The results showed that liquiritigenin significantly alleviated the slow weight gain in the high-salt group, as well as reduced the serum levels of blood urea nitrogen (BUN), blood creatinine (CRE), neutrophil gelatinase-associated lipid transport protein (NGAL) and kidney injury molecule-1 (KIM-1) as well as ameliorated the histopathological lesions in the chronic kidney injury as well as suppressed the hyper-inflammatory response and restored the protein levels associated with renal fibrosis. In vitro experimental results showed that liquiritigenin significantly inhibited the expression of KIM-1 and NGAL in HK-2 renal tubular cells, as well as the expression of inflammatory factors and fibrosis-related proteins. Mechanistically, this study is the first to demonstrate that liquiritigenin directly binds to and inhibits IRAK4, a key upstream regulator of inflammatory signaling. By suppressing IRAK4 activation, liquiritigenin effectively attenuates downstream activation of the p38 MAPK and JNK pathways. This novel mechanism highlights the potential of liquiritigenin in mitigating high salt-induced renal inflammation and fibrosis, offering new therapeutic insights for the treatment of CKD.