Mechanistic and functional characterization of ABTB2 as a novel target for pancreatic cancer therapy.

BTB/POZ domain-containing proteins are increasingly recognized for their context-dependent roles in cancer, acting as either tumor suppressors or oncogenic drivers depending on the cancer type. Among them, the function of ankyrin repeat and BTB domain-containing protein 2 (ABTB2) in pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, has remained unexplored. In this study, we employed comprehensive functional genomics approaches-siRNA/shRNA knockdown, CRISPR-Cas9 knockout, plasmid-based overexpression, and a Cre-LoxP transgenic mouse model-to systemically modulate expression in human and murine PDAC cell lines, as well as in the KPC mouse model of PDAC. Our gain- and loss-of-function studies revealed that ABTB2 plays a pivotal tumor-suppressive role, significantly impairing PDAC cell oncogenicity and tumorigenesis . Importantly, therapeutic targeting of ABTB2 using adeno-associated virus serotype 2 (AAV2) and lipid nanoparticles (LNPs) demonstrated marked anti-tumor efficacy and synergized with 5-fluorouracil (5-FU) to enhance treatment outcomes. Transcriptomic analysis, immunoprecipitation, and functional assays demonstrated that ABTB2 interacts with tumour necrosis factor receptor-associated protein 1 (TRAP1), promoting its ubiquitin-dependent degradation and thereby suppressing key oncogenic Wnt/β-catenin and PI3K/Akt signaling pathways. Notably, TRAP1 inhibitors are currently in phase I clinical trials as potential anticancer agents. Our findings provide mechanistic insight and underscore the ABTB2/TRAP1 axis as a promising therapeutic target for PDAC treatment.