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

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.