C1QBP forms a positive feedback loop with the PAICS/FAK/c-Myc axis to promote cholangiocarcinoma proliferation

Cholangiocarcinoma (CCA) is a highly lethal malignancy with increasing incidence and mortality rates worldwide. To investigate the mechanisms underlying CCA tumorigenesis, we conducted bioinformatics analysis, which revealed that C1QBP is the most upregulated membrane protein in CCA and is involved in energy metabolism, nucleotide repair, and resistance to platinum-based chemotherapeutic agents in CCA. Our findings revealed that C1QBP is significantly overexpressed in CCA and is strongly associated with increased proliferation and poor prognosis. Mechanistic studies further demonstrated that c-MYC can upregulate C1QBP expression at the transcriptional level, subsequently influencing PAICS/FAK expression and promoting CCA growth. Interestingly, C1QBP also regulates c-MYC expression by increasing FAK phosphorylation, establishing a positive feedback loop that drives tumor progression. Additionally, we developed a novel siRNA delivery system, si@LH, by encapsulating siC1QBP within hyaluronic acid-dopamine hydrogel-coated liposomes. Ex vivo experiments confirmed that this system enables prolonged and stable C1QBP inhibition. In conclusion, our study suggests that C1QBP may serve as a valuable biomarker for cholangiocarcinoma prognosis and that silencing C1QBP with si@LH, either alone or in combination with other targeted or immunotherapies, holds promise as a therapeutic strategy for cholangiocarcinoma.