IXA4 is a highly selective, nontoxic activator of IRE1/XBP1s and reduces APP secretion by activating IRE1. IXA4-stimulated IRE1 activation also enhanced pancreatic function.

In other cell lines including Huh7 and SHSY5Y cells, IXA4 selectively upregulated XBP1s mRNA relative to genes regulated by ATF6 (eg BiP) or PERK (eg CHOP). IXA4 reduces Aβ levels by 50% in conditioned medium prepared on CHO7PA2 cells expressing the V717F APP (APPV717F) mutant [1]. IXA4 rescues mitochondrial defects in SH-SY5Y cells expressing disease-associated APP mutants. After 4 h of treatment in HEK293T cells, IXA4 promotes adaptive IRE1/XBP1s signaling, but not RIDD [1]. IXA4 also promotes selective transcriptional remodeling of the ER proteostasis pathway relative to the cytoplasmic or mitochondrial pathway [1].