Novel drug target ADAM8/17 is associated with the occurrence of intrahepatic cholangiocarcinoma via Notch1/Integrinα5 pathway

Novel targeted drugs are currently available for all patients with intrahepatic cholangiocarcinoma (ICC). The goal of this study was to investigate the association between A Disintegrin and Metalloproteinase8/17 (ADAM8/17) and ICC, and to determine whether ADAM8/17 could be a novel target for ICC treatment. The expression of ADAM8/17 in ICC was analyzed using bioinformatics approaches. The occurrence and development of ADAM8/17 and its downstream pathways in ICC were analyzed using two-sample Mendelian randomization (MR) and meta-analysis. The activity of the ADAM8/17 inhibitor was evaluated using a cellular thermal shift assay (CETSA). Antitumor activity and pathway exploration were demonstrated using patient-derived organoid (PDO) models, Transwell, apoptosis assays, cell cycle assays, and western blotting. Bioinformatic analysis revealed that ADAM8 was highly expressed specifically in ICC. MR and meta-analyses have revealed that ADAM8/17 and its downstream Notch signaling pathway are closely related to the occurrence and development of ICC. Molecular docking and CETSA experiments revealed that NY-2 is a molecular inhibitor of ADAM8/17. PDO, MTT, apoptosis, and other experiments have confirmed that NY-2 inhibits the occurrence and progression of ICC. Western blotting confirmed that NY-2 regulates Notch1–HIF1α–VEGFA and Integrinα5–TGFβ–Smad signaling pathways to exert anti-ICC effects. This study revealed that high ADAM8/17 expression is associated with poor prognosis in patients with ICC, ADAM8/17 is a novel antitumor target, and NY-2, a small-molecule compound that targets ADAM8/17, significantly inhibits the occurrence and progression of ICC via Notch1–HIF1α–VEGFA and Integrinα5–TGFβ–Smad signaling pathways. Future research aims to confirm the targeting and clinical application value of compounds through gene editing and orthotopic liver tumor models.