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 demonstrated 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 attenuating lipid accumulation induced by free fatty acids (FFAs) in L-02 cells. Further investigation revealed that G15's mitigation of ERS was primarily achieved by suppressing the levels of inositol-requiring enzyme 1 (IRE1). Western blot analysis confirmed that G15 effectively down-regulated IRE1 protein expression and decreased the expression levels of its downstream X-box binding protein 1 (XBP1) and signal transducer and activator of transcription 3 (STAT3) proteins, thereby reducing cellular lipid accumulation. In addition, G15 treatment inhibited FFA-induced nitric oxide (NO) production in a concentration-dependent manner and suppressed the secretion of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α. Collectively, these findings underscore that G15 has the potential to be a leading candidate for the treatment of NASH by down-regulating the IRE1/XBP1/STAT3 signaling pathway.