STAT1 Mediates FAK-Driven Choline Metabolism and Metastasis in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by early dissemination, rapid progression, and poor prognosis. Focal adhesion kinase (FAK) has been implicated in PDAC metastasis, but its downstream mediators remain incompletely defined. Choline kinase alpha (CHKα), a key enzyme in choline metabolism, has been recognized as a pro-metastatic factor; however, the regulatory mechanisms linking FAK to CHKα expression are not fully understood. We employed correlation analysis, structural modeling, immunofluorescence, co-immunoprecipitation, and functional assays to investigate the role of STAT1 in the FAK-CHKα axis. The impact of CHKα inhibition was evaluated in vitro and in vivo . The anti-metastatic efficacy of CHKI-03, the CHKα inhibitor developed by our team, and reference compound RSM-932A were compared through intrasplenic injection liver metastasis model. STAT1 was identified as a critical mediator of the FAK-CHKα axis. FAK directly interacted with STAT1 and modulated its expression. Silencing STAT1 reduced CHKA expression at both mRNA and protein levels and attenuated FAK-driven cell migration and invasion. ChIP-Atlas analysis revealed STAT1 binding at the CHKA locus, suggesting direct transcriptional regulation. In vivo , CHKI-03 effectively suppressed PDAC liver metastasis. Our findings establish STAT1 as a key mediator in the FAK-CHKα axis, driving PDAC liver metastasis. Targeting CHKα with CHKI-03 offers a promising anti-metastatic therapeutic strategy with superior efficacy.