IXA4 is a specific activator of IRE1/XBP1s signalling activator, promotes IRE1-dependent XBP1 splicing, selective activates the IRE1/XBP1s signaling. IXA4 does not affect the UPR or other stress-responsive signaling pathways. IXA4 increases IRE1 RNase activity through a mechanism independent of binding the IRE1 nucleotide-binding pocket. IXA4 is distinct from currently available IRE1 activators, which bind the kinase active site. IXA4 improves ER proteostasis of AD-relevant APP mutants, reducing the secretion of Aβ through the increased targeting of APP to degradation. IXA4 reduces mitochondrial dysfunction associated with mutant APP overexpression, likely reflecting the reduced intracellular APP afforded by compound treatment.
