DTX3L Promotes Intrahepatic Cholangiocarcinoma Progression Through P53 Ubiquitination-Mediated Inhibition of ER Stress and Apoptosis

Background: Deltex E3 ubiquitin ligase 3L (DTX3L) is implicated in the progression of various cancer types; however, its specific contribution to intrahepatic cholangiocarcinoma (ICC) remains unexplored. Therefore, this study sought to investigate the involvement of DTX3L in ICC development and elucidate its regulatory effect on endoplasmic reticulum stress (ERS) and apoptosis via P53 ubiquitination. Methods: We systematically evaluated DTX3L expression in ICC samples using qRT-PCR and Western blotting. Functional assays, including Cell Counting Kit-8 (CCK-8), colony formation, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and flow cytometry, were performed to assess cell proliferation and apoptosis. Co-immunoprecipitation and ubiquitination assays were employed to investigate the interaction between DTX3L and P53. <i>In vivo</i>, tumor xenograft models were used to examine the effects of DTX3L knockdown on tumor growth and ERS pathway activation. Results: DTX3L was significantly overexpressed in ICC tissues and cells (<i>p</i> < 0.05), and its overexpression promoted proliferation, suppressed apoptosis, and downregulated ERS-associated markers, including phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α), protein kinase R-like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP), and activating transcription factor 4 (ATF4) (<i>p</i> < 0.01). Mechanistically, DTX3L directly interacted with P53 and enhanced its ubiquitination and degradation, attenuating its tumor-suppressive effects. Knockdown of DTX3L significantly activated ERS signaling and induced apoptosis (<i>p</i> < 0.01), the effects were reversed by simultaneous P53 knockdown (<i>p</i> < 0.01). Conclusion: DTX3L is a critical oncogene in ICC progression by promoting P53 ubiquitination-mediated suppression of ERS and apoptosis. These findings suggest that DTX3L may serve as a promising therapeutic target in ICC.