Novel Glycyrrhetin\nUreas Possessing 2‑Hydroxy-3-enone\nA Ring: Modification, Anti-inflammatory Activity, and Targeted STING\nfor the Remedy of Acute Kidney Injury

Glycyrrhetin urea has emerged as a privileged scaffold\nwith anti-inflammatory\nactivity for the treatment and prevention of acute kidney injury (AKI).\nIn this study, structural modifications of the A ring of glycyrrhetinic\nacid 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\nheat shift assay and to inhibit the STING/NF-κB pathway in RAW264.7\ncells. It acted on the STING pathway, inhibited NF-κB phosphorylation,\nand subsequently reduced the level of release of inflammatory factors.\nAdditionally, <b>7o</b> significantly increased the survival\nrate of renal tubular epithelial cells, demonstrating a protective\neffect against cisplatin-induced cell death and mitigating inflammation\nactivation. The <i>in vivo</i> AKI mouse model showed that <b>7o</b> significantly downregulated serum creatinine (Scr), blood\nurea nitrogen (BUN), and levels of inflammatory factors (IL-1β,\nIL-6, and TNF-α), thereby improving renal function. Morphological\nanalysis revealed that <b>7o</b> attenuated the cisplatin-induced\nrenal tubular injury. Therefore, <b>7o</b> represents a promising\nlead for the prevention and treatment of AKI.