Targeting UGCG sensitizes AML cells to venetoclax through RAB32-mediated endoplasmic reticulum-mitochondria communication

Summary Uridine diphosphate (UDP)-glucose ceramide glucosyltransferase (UGCG) is an enzyme that glycosylates ceramide and blunts its pro-apoptotic activity in cancer cells. Targeting UGCG sensitizes solid cancer cells to chemotherapy. However, whether targeting UGCG can sensitize acute myeloid leukemia (AML) cells to venetoclax remains unclear. Here, we found that the inhibition of UGCG genetically or with its inhibitor eliglustat efficiently suppressed growth and promoted apoptosis in AML cells. Moreover, eliglustat in combination with venetoclax increased apoptosis, reduced AML cell viability, and inhibited AML effectively both for primary AML cells and xenograft models. Mechanistically, the combination induced ceramide accumulation, which activated the endoplasmic reticulum (ER) stress-GRP78/PERK/CHOP axis. Interestingly, combinatory treatment activated RAB32, which led to mitochondrial fission through ER-mitochondria communication and DRP1 activation. These findings demonstrate that targeting UGCG in combination with venetoclax is an alternative combinatory strategy to treat AML and provide insights into ceramide-mediated cell death in anti-cancer therapies.