TYROBP facilitates metastatic progression in pancreatic cancer through CTSZ-driven glycolytic rewiring and macrophage recruitment.

Pancreatic ductal adenocarcinoma (PDAC) remains intractable because metastasis outruns intervention. Here we define TYROBP-a microglial adaptor previously unlinked to PDAC-as a pivotal metastatic driver. Transcriptomic mining and validation across paired human specimens revealed pronounced TYROBP up-regulation that trended with poorer survival. Gain- and loss-of-function studies showed that TYROBP potentiates PDAC cell migration and invasion without influencing proliferative indices in vitro or subcutaneous tumor growth in vivo. Mechanistically, transcription factor SP1 occupies a promoter motif (P1) to enforce TYROBP expression; TYROBP then complexes with cathepsin Z (CTSZ), enhancing CXCL8-mediated tumor-associated macrophage recruitment and activating a pAKT-CD44 axis independent of epithelial-to-mesenchymal transition while simultaneously accelerating glycolysis. The flavonoid baicalein engages TYROBP directly, abrogates CTSZ/pAKT/CD44 signaling, and curtails hepatic metastasis in mice without systemic toxicity. TYROBP knock-down blunts dissemination, whereas enforced TYROBP expression exacerbates metastasis-effects reversed by baicalein. Thus, the SP1-TYROBP-CTSZ axis licenses PDAC metastasis, and baicalein-mediated TYROBP inhibition offers a tractable therapeutic strategy.