Background: Aberrant protein O-fucosylation mediated by protein O-fucosyltransferase 1 (POFUT1), has emerged as a hallmark of tumorigenesis that regulates key signaling pathways, including Notch, which is frequently dysregulated in cancers. Protein O-fucosylation, catalyzed by POFUT1, regulates Notch signaling and has been implicated in individual cancers, but its pan-cancer expression patterns, clinical significance, and relationship to tumor immunity remain incompletely characterized. Methodology: We conducted a multi-omics bioinformatics analysis using TCGA and other public datasets to evaluate POFUT1 expression across 33 cancer types (n > 10,000). Differential expressions, tumor stage correlations, and survival outcomes were assessed. Immune cell infiltration was estimated using SangerBox and TIMER algorithms, while promoter methylation patterns were analyzed through UALCAN. Functional enrichment and protein–protein interaction networks were constructed to elucidate functional mechanism. Western blot validation in prostate and ovarian cancer cell lines confirmed our computational analysis. Results: POFUT1 showed significant overexpression in 16 of 33 cancer types (FDR-adjusted p < 0.05), with the highest elevation in BRCA (breast invasive carcinoma; log2FC = 2.31) and LUAD (lung adenocarcinoma; log2FC = 2.1). A high POFUT1 expression correlated with poor overall survival in eight cancer types (HR range: 1.8–3.2, p < 0.01) and disease-free survival in seven cancers. POFUT1 levels positively correlated with myeloid-derived suppressor cells (MDSCs) infiltrating in 15 cancer types, while inversely correlated with natural killer T (NKT) cells presence in 15 cancers (mean R = −0.34, p < 0.05), indicating an association with immunosuppressive microenvironments. Promoter hypomethylation in tumors suggested epigenetic dysregulation as a potential driver of its overexpression. Western blot analysis confirmed POFUT1 protein upregulations in prostate and ovarian cancer cell lines (1.7–2.1-fold. p < 0.01), corroborating transcriptomic findings. Conclusion: This pan-cancer study establishes POFUT1 as a critical oncogenic factor linked to aggressive disease, immune evasion, and poor prognosis. Its consistent overexpression and functional impact highlight its potential as a biomarker and target for anticancer therapy. While these computational findings require experimental validation, POFUT1 emerges as a candidate biomarker warranting functional studies and potential therapeutic targeting.

Dauricine has been shown to possess intriguing anti-cancerous activities against various malignancies. The current study examined the inhibitory effects of dauricine against lung adenocarcinoma with cell lines and animal models. MTT assay was performed in three different lung adenocarcinoma cell lines using a concentration range of dauricine. Colony formation, wound healing, Edu incorporation, and cell cycle analysis were conducted to investigate the impact of dauricine on lung adenocarcinoma cells in vitro. Moreover, flow cytometry was performed to observe the effect of dauricine on cellular ROS levels. The expression of redox regulator Nrf2 and apoptosis-related markers was assessed by Western blot. Importantly, the anti-tumor efficacy of dauricine was studied in vivo with two lung adenocarcinoma animal models, including a subcutaneous cell line-derived syngeneic model and an inducible orthotopic KRAS^G12D-driven lung adenocarcinoma model. The proliferation and migration of lung adenocarcinoma cells were significantly reduced by dauricine treatment. Flow cytometry analysis revealed that dauricine treatment resulted in cell cycle arrest at G0/G1 phases in A549, H1299, and A427 cells. Intracellular ROS levels were markedly augmented by dauricine treatment. Notably, dauricine led to the downregulation of the master redox regulator Nrf2. Meanwhile, dauricine treatment resulted in decreased Bcl-2 levels but elevated expression of BAX and cleaved Caspase 3. Finally, dauricine demonstrated significant efficacy in restricting tumor progression in both subcutaneous syngeneic and orthotopic lung adenocarcinoma models. Our results corroborate the anti-cancer effects of dauricine against lung adenocarcinoma with in vivo and in vitro analyses. Our findings also provide mechanistic evidence that links the impact of dauricine to cell cycle blockage and ROS-mediated apoptosis.