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

Abstract 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 developed 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 improved survival and reduced tunicamycin-induced ER-stress markers. In Drosophila , S88 ameliorated neuromuscular and locomotor phenotypes in a UBQLN2-associated ALS model and improved 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. Graphical abstract Structure-informed screening guided by ERO1A prioritized five natural products for functional validation across cellular and Drosophila models. The pyrazolopyridine alkaloid S88 consistently reduced ER-stress markers, improved neuronal survival, rescued locomotor and neuromuscular defects in an ALS model, and ameliorated aging phenotypes. The direct molecular target of S88 remains to be defined. Generated with assistance from the AI-based visualization tool NotebookLM and refined by the authors.