TAGLN2 promotes mesenchymal circulating tumor cell-associated metastasis through the CSNK1E-YAP Axis with concomitant EMT induction and metabolic remodeling in hepatocellular carcinoma.

Postoperative recurrence and hematogenous metastasis remain major barriers to long-term survival in hepatocellular carcinoma (HCC). Mesenchymal circulating tumor cells (mCTCs) are closely associated with HCC recurrence and metastasis, yet the key regulatory mechanisms and accompanying circulating metabolic alterations remain unclear. Here, we integrated TCGA-LIHC data, clinical tissues, peripheral blood samples from patients with HCC, plasma 1H NMR metabolomics, in vitro functional assays, protein-interaction analyses, rescue experiments, and a nude mouse lung metastasis model to investigate the role and mechanism of TAGLN2 in mCTC-associated HCC metastasis. TAGLN2 was significantly upregulated in HCC tissues, tumors from CTC-positive patients, and mCTCs, and was associated with portal vein tumor thrombus, higher Edmondson grade, postoperative recurrence, and poor prognosis. Multivariate Cox analysis indicated that TAGLN2 positivity in mCTCs was an independent risk factor for postoperative recurrence. Plasma 1H NMR metabolomics revealed detectable circulating metabolic alterations in patients with HCC, mainly involving lipoprotein remodeling, lipid transport, membrane lipid metabolism, and energy metabolism; these high-VIP metabolic features partially overlapped with pathways enriched in TAGLN2-high/CTC-high and TAGLN2-high/mCTC-high states. Functionally, TAGLN2 promoted EMT, migration, invasion, and sphere formation, whereas TAGLN2 silencing suppressed these prometastatic phenotypes and reduced lung metastatic burden in vivo. Mechanistically, TAGLN2 interacted with CSNK1E and enhanced its protein stability, thereby promoting YAP nuclear translocation and activating EMT-associated phenotypes; CSNK1E inhibition partially reversed TAGLN2-induced prometastatic effects. Collectively, TAGLN2 promotes mCTC-associated hematogenous metastasis in HCC through the CSNK1E-YAP axis, and plasma 1H NMR metabolic signatures may serve as complementary liquid-biopsy signals for identifying TAGLN2-associated CTC/mCTC-high metastatic states.