Discovery of a pyrazolopyridine alkaloid that mitigates neuronal ER stress and age-related decline.

Endoplasmic reticulum (ER) stress contributes to the pathogenesis of neurodegenerative and age-associated diseases, motivating the search for compounds that enhance ER-stress resilience. Modulation of ER-redox pathways, including those associated with the oxidase ERO1A, can attenuate maladaptive unfolded protein response (UPR) signaling and improve cellular stress tolerance. Here we develop an integrative discovery strategy to identify natural compounds that mitigate ER-stress-associated phenotypes across cellular and organismal models. Structure-informed virtual screening guided by ERO1A biology prioritized the pyrazolopyridine alkaloid S88. In human SH-SY5Y-derived neurons, S88 improves survival and reduces tunicamycin-induced ER-stress markers. In Drosophila, S88 ameliorates neuromuscular and locomotor phenotypes in a UBQLN2-associated ALS model and improves aging-related outcomes. Biochemical assays did not detect inhibition of ERO1A or radical scavenging activity by S88, indicating that its molecular target remains to be identified. Together, these findings identify S88 as a natural-product scaffold that enhances ER-stress resilience across neuronal and in vivo models.