VCP inhibition induces rapid cell death through ER stress driven actin cytoskeletal collapse

The endoplasmic reticulum (ER) maintains cellular proteostasis through the unfolded protein response (UPR), whereas excessive or unresolved stress can rapidly compromise cell viability. Beyond the well characterized transcriptional programs, how ER stress acutely remodels cellular architecture to induce cell death remains poorly understood. Here, we report the rational design of a nucleoside-based small molecule inhibitor of the AAA-ATPase VCP (NY-1), which forms a stable host-guest complex with β-cyclodextrin. NY-1 induces robust ER stress and a strikingly rapid form of cell death characterized by actin cytoskeletal collapse and synchronized membrane blebbing. We identify a non-transcriptional signaling pathway in which ER stress activated IRE1α remodels the 14-3-3 interactome, releasing and activating the phosphatase SSH1, thereby promoting cofilin dephosphorylation and F-actin disassembly. Chemical chaperone treatment restores cytoskeletal integrity and cell viability, demonstrating a direct causal link between ER proteostasis disruption and actin network collapse. These findings reveal an acute ER stress signaling axis controlling actin dynamics and establish NY-1 as a chemical probe for dissecting rapid cell death programs.