The neuroprotective effect of Cucurbitacin B against Aβ and tau toxicities requires functional HDAC6 and stress granule pathways.

Alzheimer's disease (AD) is characterized by proteostasis collapse driven by amyloid-β (Aβ) plaques and tau tangles. Dysregulation of stress granule (SG) dynamics and aberrant histone deacetylase 6 (HDAC6) activity are emerging as pivotal pathogenic mechanisms promoting neurodegeneration. Here, we identify that Cucurbitacin B (CB), a natural triterpenoid, acts as a potent SG inducer that confers broad-spectrum neuroprotection. Mechanistically, we demonstrate a novel "recruit-and-sequester" model: CB promotes the assembly of HDAC6-recuited SGs, thereby physically sequestering HDAC6 and functionally inhibiting its deacetylase activity. In Caenorhabditis elegans (C. elegans) and mammalian cell models, CB treatment significantly alleviated Aβ oligomer-induced cytotoxicity and tau hyperphosphorylation. Notably, the neuroprotective efficacy of CB was abolished by the genetic knockdown of core SG components (gtbp-1/G3BP1, tiar-1/TIA1) or hda-6/HDAC6, confirming that its therapeutic action relies on the integrity of the HDAC6-SG. Our findings highlight the potential of modulating SG dynamics to spatially regulate HDAC6, offering a novel therapeutic strategy for AD.