Novel Glycyrrhetin Ureas Possessing 2-Hydroxy-3-enone A Ring: Modification, Anti-inflammatory Activity, and Targeted...

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 7o exhibited the most promising anti-inflammatory activity. 7o 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, 7o significantly increased the survival rate of renal tubular epithelial cells, demonstrating a protective effect against cisplatin-induced cell death and mitigating inflammation activation. The in vivo AKI mouse model showed that 7o 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 7o attenuated the cisplatin-induced renal tubular injury. Therefore, 7o represents a promising lead for the prevention and treatment of AKI.