GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. The catalysis of BH4 biosynthesis is tightly regulated for physiological neurotransmission, inflammation, and vascular tone. Paradoxically, BH4 has emerged as an oncometabolite regulating tumor growth, but the effects on tumor development remain controversial. Here, we found that GCH1 potentiated the growth of triple-negative breast cancer (TNBC) and HER2+ breast cancer and transformed nontumor breast epithelial cells. Independent of BH4 production, GCH1 protein induced epithelial-to-mesenchymal transition by binding to vimentin (Vim), which was mediated by HSP90. Conversely, GCH1 ablation impaired tumor growth, suppressed Vim in TNBC, and inhibited EGFR/ERK signaling while activating the p53 pathway in estrogen receptor–positive tumor cells. GCH1 deficiency increases tumor cell sensitivity to HSP90 inhibition and endocrine treatments. In addition, high GCH1 correlated with poor breast cancer survival. Together, this study reveals an enzyme-independent oncogenic role of GCH1, presenting it as a potential target for therapeutic development. Significance: GTP cyclohydrolase functions as an oncogene in breast cancer and binds vimentin to induce epithelial-to-mesenchymal transition independently of its enzyme activity, which confers targetable vulnerabilities for developing breast cancer treatment strategies.

Oncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

Bestrophin isoform 4 (BEST4) is a newly identified subtype of the calcium-activated chloride channel family. Analysis of colonic epithelial cell diversity by single-cell RNA-sequencing has revealed the existence of a cluster of BEST4+ mature colonocytes in humans. However, if the role of BEST4 is involved in regulating tumour progression remains largely unknown. In this study, we demonstrate that BEST4 overexpression attenuates cell proliferation, colony formation, and mobility in colorectal cancer (CRC) in vitro, and impedes the tumour growth and the liver metastasis in vivo. BEST4 is co-expressed with hairy/enhancer of split 4 (HES4) in the nucleus of cells, and HES4 signals BEST4 by interacting with the upstream region of the BEST4 promoter. BEST4 is epistatic to HES4 and downregulates TWIST1, thereby inhibiting epithelial-to-mesenchymal transition (EMT) in CRC. Conversely, knockout of BEST4 using CRISPR/Cas9 in CRC cells revitalises tumour growth and induces EMT. Furthermore, the low level of the BEST4 mRNA is correlated with advanced and the worse prognosis, suggesting its potential role involving CRC progression.

The 11th revision of the International Statistical Classification of Disease and Related Health Problems and Cholangiocarcinoma Shijie Cai, Shivan Sivakumar

Objective: This study aimed to systematically compare the short-term outcomes of minimally invasive pancreatic enucleation (MI-pEn), including laparoscopic and robotic-assisted approaches, and open pancreatic enucleation (O-pEn). Methods: A systematic search of PubMed, MEDLINE, Embase, and Web of Science was conducted for studies published between January 1990 and December 2025 that compared various types of pancreatic enucleation. The literature screening, data extraction, and quality assessment followed the PRISMA guidelines. The meta-analysis was performed using RevMan 5.4.1 and R 4.3.0. Results: Fifteen studies were included, with thirteen comparative studies (463 MI-pEn, 547 O-pEn) incorporated into the meta-analysis. Two studies comparing laparoscopic and robot-assisted enucleation were also included. No significant difference in clinically relevant postoperative pancreatic fistula (CR-POPF) was detected between MI-pEn and O-pEn (OR = 0.78; 95% CI: 0.56–1.07; p = 0.12). However, MI-pEn was associated with significantly reduced operation time (MD = −21.24; p = 0.01), blood loss (MD = −75.88; p < 0.00001), hospital stay (MD = −2.07; p = 0.001), and wound infection (OR = 0.3; p = 0.03). Direct comparisons between robotic and laparoscopic enucleation revealed no significant differences in any outcomes. Conclusions: MI-pEn is safe and feasible and offers advantages in terms of operative time, blood loss, and recovery without increasing complications. Robotic and laparoscopic approaches yield comparable short-term outcomes in pancreatic enucleation, although the potential advantage of robotic surgery in reducing pancreatic fistula risk warrants further validation.

Supplementary Figures from GTP cyclohydrolase drives breast cancer development and promotes EMT in an enzyme-independent manner