Novel Glycyrrhetin Ureas Possessing 2-Hydroxy-3-enone A Ring: Modification, Anti-inflammatory Activity, and Targeted STING for the Remedy of Acute Kidney Injury

Glycyrrhetin urea has emerged as a privileged scaffold with anti-inflammatory activity for the treatment and prevention of acute kidney injury (AKI). In this study, structural modifications of the A ring of glycyrrhetinic acid yielded a series of urea derivatives, among which compound <b>7o</b> exhibited the most promising anti-inflammatory activity. <b>7o</b> was confirmed to interact with STING through a cellular heat shift assay and to inhibit the STING/NF-κB pathway in RAW264.7 cells. It acted on the STING pathway, inhibited NF-κB phosphorylation, and subsequently reduced the level of release of inflammatory factors. Additionally, <b>7o</b> significantly increased the survival rate of renal tubular epithelial cells, demonstrating a protective effect against cisplatin-induced cell death and mitigating inflammation activation. The <i>in vivo</i> AKI mouse model showed that <b>7o</b> significantly downregulated serum creatinine (Scr), blood urea nitrogen (BUN), and levels of inflammatory factors (IL-1β, IL-6, and TNF-α), thereby improving renal function. Morphological analysis revealed that <b>7o</b> attenuated the cisplatin-induced renal tubular injury. Therefore, <b>7o</b> represents a promising lead for the prevention and treatment of AKI.