Targeting VPS41 induces methuosis and inhibits autophagy in cancer cells

The homotypic fusion and vacuole protein sorting (HOPS) complex mediates membrane trafficking involved in endocytosis, autophagy, lysosome biogenesis, and phagocytosis. Defects in HOPS subunits are associ-ated with various forms of cancer, but their potential as drug targets has rarely been examined. Here, we iden-tified vacuolar protein sorting-associated protein 41 homolog (VPS41), a subunit of the HOPS complex, as a target of methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP), a natural small mole-cule with preferable anticancer activity. DMBP induced methuosis and inhibited autophagic flux in cancer cells by inhibiting the function of VPS41, leading to the restrained fusion of late endosomes and autophago-somes with lysosomes. Moreover, DMBP effectively inhibited metastasis in a mouse metastatic melanoma model. Collectively, the current work revealed that targeting VPS41 would provide a valuable method of in-hibiting cancer proliferation through methuosis.