HMGA2 Stabilizes hnRNPK to Drive YAP-Dependent Liver Metastasis in Pancreatic Cancer.

Pancreatic cancer (PC) is a highly aggressive malignant neoplasm with a propensity for liver metastasis (LM), which significantly contributes to poor patient prognosis, but its molecular mechanism remains incompletely elucidated. In this study, we demonstrated that high mobility group protein A2 (HMGA2) is markedly elevated in LM tissues and circulating tumor cells (CTCs) of PC patients. Mechanistically, HMGA2 binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) via "AT-hook" functional motif, suppressing its ubiquitination to block proteasomal degradation. This interaction promotes the transcriptional activation of Yes-associated protein (YAP) by facilitating hnRNPK binding to the YAP promoter and thereby enhancing metastatic potential of PC. Functional assays validate that hnRNPK mediates HMGA2's pro-metastatic function, and YAP acts as the indispensable downstream effector of this cascade. Our findings establish the HMGA2/hnRNPK-YAP axis as a critical regulator of LM and propose targeting this pathway as a promising therapeutic strategy for metastatic PC.