Design and synthesis of hederagenin derivatives modulating STING/NF-κB signaling for the relief of acute liver injury in septic mice

Systemic inflammatory responses often result in sepsis and inhibition of inflammation is one strategy for sepsis treatment. In this study, we designed and synthesized 32 novel hederagenin (HD) derivatives with modifications at the A-ring, C-28, and C-23 positions and screened their anti-inflammatory activities in vitro, finding multiple compounds with potential anti-inflammatory activity. Of these, compound 1 was the most effective and was used for subsequent investigations into its mechanism of action and in vivo activity. In vivo assessments of anti-inflammatory activity showed that compound 1 reduced inflammation in a mouse model of sepsis with acute liver injury caused by lipopolysaccharide (LPS). Compound 1 also inhibited STING, p-IRF3, p-TBK1, p-p65, and p-IκB proteins in cGAS-STING-associated signaling. These findings indicated that compound 1 reduced inflammation through inhibition of STING expression and hence reducing activation of STING and nuclear factor-κB (NF-κB) signaling. Our work demonstrated that compound 1 is a promising lead compound for designing and developing anti-sepsis drugs.