AP1S3 Promotes Proliferation and Invasion of Cholangiocarcinoma Cells and Modulates HER2 Trafficking

Background: Cholangiocarcinoma (CCA) is an inflammation-associated malignancy with limited benefit from HER2-targeted therapy. Whether psoriasis is causally linked to CCA and how AP1S3 contributes remain unclear. Methods: We performed exploratory two-sample Mendelian randomization (MR), integrated bulk and single-cell transcriptomes, and used CCA cell lines and xenografts to examine AP1S3 and HER2 trafficking. Results: Strict MR (8 IVs; MHC excluded) gave an OR of 1.00 (95% CI 0.83–1.21; p = 0.98); the relaxed-threshold estimate (OR 1.12, 1.01–1.25; p = 0.037) was not robust (independent OR 1.05, 0.96–1.14; p = 0.30). IL-17A/TNF-α increased AP1S3 in CCA cells and activated NF-κB/RELA, but direct RELA binding was not demonstrated. AP1S3 was associated with a SCEL+ squamous-like program. AP1S3 co-precipitated with HER2 via EIPDLL (residues 930–935, kinase domain) and modulated HER2 trafficking; direct binding, isoform specificity and active recycling were not established. Conclusions The psoriasis–CCA association is inconclusive. AP1S3 is a candidate inflammatory regulator of HER2 trafficking and requires direct binding, loss-of-function and clinical validation.