Synthesis and biological evaluations of novel 18β-glycyrrhetinic acid derivatives as histone deacetylase 3 degraders with anti-inflammatory effects.

Histone deacetylase 3 (HDAC3) is implicated in inflammatory signaling, and its degradation represents a promising anti-inflammatory strategy. Based on the 18β-glycyrrhetinic acid analogue COOTO-Me, we designed and synthesized a series of novel derivatives and identified Z8 as a potent HDAC3 degrader. In THP-1 cells, Z8 induced dose- and time-dependent HDAC3 degradation. Multi-omics analysis indicated enrichment of the NOD-like receptor pathway, and Z8 suppressed the maturation of IL-1β and caspase-1 in PMA-differentiated THP-1 macrophages, indicating NLRP3 inflammasome inhibition. Z8 showed favorable pharmacokinetics profiles in rats, including high intraperitoneal bioavailability. In vivo, Z8 prolonged survival in LPS-induced septic shock, and alleviated DSS-induced colitis with less weight loss, preserved colon length and restored intestinal barrier function. These results established Z8 as a novel HDAC3 degrader with excellent anti-inflammatory activity.