Development of New Genipin Derivatives as Potential NASH Treatments: Design, Synthesis and Action Mechanism

Nonalcoholic steatohepatitis (NASH) is a multifaceted liver disease. Endoplasmic reticulum stress (ERS), a key driver in NASH pathogenesis, triggers metabolic irregularities, liver steatosis, and inflammation. Genipin, an iridoid from the traditional Chinese medicine Gardenia jasminoides, has shown significant effects against ERS. In the current work, 33 new genipin derivatives were designed and synthesized to evaluate their potential to treat NASH. Notably, G15 emerged as the most potent candidate, significantly reducing lipid accumulation induced by free fatty acids (FFAs) in L-02 cells. Further investigation indicated that G15's alleviation of ERS primarily involved the inositol-requiring enzyme 1(IRE1) signaling pathway, and that G15 can effectively down-regulate the IRE1 protein level. The downstream expression of X-box binding protein 1(XBP1) and signal transducer and activator of transcription 3(STAT3) proteins are confirmed by Western blot analysis. The results showed that G15 treatment inhibited FFA-induced nitric oxide (NO) production in a concentration-dependent manner, and decreased the production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Collectively, these findings underscore G15's potential as a leading candidate in the development of therapeutics for the treatment of NASH, with IRE1 inhibition being a viable target for intervention.