ATI-1 mediated disruption of the VCP-UFL1-Beclin1 axis thwarts autophagy initiation to trigger metabolic catastrophe in autophagy-addicted cancers

Targeting Autophagy initiation represents a promising strategy to disrupt the metabolic resilience of Cancer cells. In this study, we identified ATI-1 as a novel small-molecule inhibitor that selectively blocks the early stages of autophagosome formation. Importantly, we discovered that ATI-1-mediated de novo inhibition of Autophagy initiation leads to a synergistic surge in cell death under nutrient-deprived conditions, revealing a critical, context-specific vulnerability in autophagy-dependent malignancies. Mechanistically, ATI-1 appears to target valosin-containing protein (VCP/p97) and disrupt its interaction with the UFM1-specific E3 Ligase UFL1. This disruption may promote the polyubiquitination and subsequent degradation of Beclin1, thereby contributing to the inhibition of Autophagy initiation. Furthermore, ATI-1 demonstrates potent antitumor efficacy in xenograft models with minimal overt toxicity. This work collectively suggests that the VCP-UFL1-Beclin1 axis may represent a potentially targetable node in Autophagy regulation, and identifies ATI-1 as a potential small-molecule modulator of this pathway, thereby providing a promising therapeutic lead for Cancer treatment.

Antitumor efficacy; Inhibition of autophagy initiation; Small-molecule inhibitor; VCP–UFL1–Beclin1 axis.