Asperuloside promotes innate immunity via IRE-1/XBP-1 mediated unfolded protein response

Numerous studies have reported that asperuloside (ASP), a monomeric compound extracted from the traditional Chinese medicine Spreading Hedyotis Herb, possesses a variety of medicinal properties, including the treatment of obesity, cancer, inflammatory diseases, and bacterial infections. However, its role in innate immunity and the underlying mechanisms of action remain largely unexplored. Protein homeostasis and the health of the endoplasmic reticulum (ER) are crucial for organismal function, as a well-balanced ER is essential not only for maintaining cellular integrity but also for ensuring immune homeostasis. In this study, we demonstrated that asperuloside enhances the resistance of Caenorhabditis elegans to the human opportunistic pathogen Pseudomonas aeruginosa PA14 and reduces the bacterial load within its intestine. Additionally, asperuloside promotes innate immunity by activating the IRE-1/XBP-1 signaling pathway. Furthermore, asperuloside protects A549 human lung epithelial cells and mice against PA14 infection through the IRE-1/XBP-1 signaling pathway. Our findings indicate that the ability of asperuloside to promote innate immunity is conserved across invertebrates and mammals, offering new insights for the future development of antibacterial drugs.