Circulating NSUN6 serves as a prognostic biomarker for early metastasis in HCC via hippo pathway modulation.

BACKGROUND: Portal vein tumor thrombus is a lethal complication of HCC for which effective biomarkers are urgently needed. METHODS: Through proteomic profiling, functional and mechanistic assays, and machine learning-based evaluation of serum NSUN6 in 472 HCC patients with external validation (n = 98), we characterized an epitranscriptomic regulator of HCC metastasis. RESULTS: NSUN6 was downregulated in PVTT and suppressed metastasis by catalyzing m⁵C modification of SAV1 mRNA, stabilizing its transcript and activating Hippo signaling. Furthermore, NSUN6 was released from HCC cells via extracellular vesicle-associated and non-canonical pathways. Circulating NSUN6 levels were inversely associated with metastasis in both discovery and validation cohorts, and lower levels predicted shorter metastasis-free survival. CONCLUSION: Our findings establish the NSUN6-SAV1-YAP axis as a key epitranscriptomic tumor-suppressive mechanism and support circulating NSUN6 as a potential biomarker for early risk stratification in HCC.