SRGN-mediated reactivation of the YAP/CRISPLD2 axis promotes aggressiveness of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major contributor to global cancer-related mortality. Serglycin (SRGN) is involved in the progression of various cancers, and its overexpression is related to poor prognosis in HCC patients. Its biological role in HCC aggressiveness is unknown. This study aims to elucidate the mechanism of SRGN in HCC. Via in vitro and vivo experiments, we identified SRGN as a critical regulator of HCC cells migratory capability and metastasis. SRGN significantly correlated with maintaining stemness-like characteristics, emphasizing its central role in HCC progression. Mechanistically, SRGN activated YAP into the tumor cells' nucleus. Moreover, SRGN selectively upregulated CRISPLD2, establishing the SRGN/YAP/CRISPLD2 axis and promoting metastatic behavior in HCC cells. Our results revealed that CRISPLD2 is a direct target of the SRGN-mediated YAP/TEAD1 complex. SRGN orchestrated stemness maintenance, tumorigenesis, and metastasis in an autocrine way by selectively reactivating the novel YAP/CRISPLD2 axis. Besides, sorafenib with verteporfin showed a certain therapeutic effect in SRGN-positive individuals. Our work clarifies the mechanism by which SRGN promotes the invasiveness of HCC. It provides insights into targeting the SRGN-triggered signaling pathway as a potential new direction in treating HCC.