Betulinic Acid Alleviates Lipopolysaccharide-Induced Hepatic Inflammatory Injury by Inhibiting the RIG-I/NF-κB Signaling Pathway

Abstract Betulinic acid (BA), a natural pentacyclic triterpenoid, possesses anti-inflammatory and antioxidant properties. However, its role and mechanisms in lipopolysaccharide (LPS)-induced liver injury remain unclear. We assessed BA’s protective effects in LPS-challenged piglets and AML12 cells. Our results demonstrated that BA pretreatment significantly mitigated liver pathology and decreased pro-inflammatory cytokines in LPS-challenged piglets. Transcriptomics and Western blot results revealed that BA pretreatment markedly reduced LPS-induced hepatic inflammatory injury in piglets by suppressing the retinoic acid-inducible gene I (RIG-I)/nuclear factor-κB (NF-κB) pathway. Consistently, BA blocked activation of the RIG-I/NF-κB cascade to alleviate LPS-induced inflammatory damage in AML12 cells. Notably, the RIG-I agonist polyinosinic-polycytidylic acid (poly I:C) substantially counteracted BA’s protective effects in AML12 cells by enhancing activation of the RIG-I/NF-κB cascade. In conclusion, BA attenuated LPS-induced liver inflammatory injury by inhibiting RIG-I-mediated NF-κB activation. This finding provides a theoretical foundation and identifies a new target for BA-mediated therapy for liver injury.