LOXL2 and SYVN1 cooperate across cellular compartments to drive liver hepatocellular carcinoma progression.

[BACKGROUND] The synergistic interplay between extracellular matrix (ECM) remodeling and proteostatic adaptation in the progression of liver hepatocellular carcinoma (LIHC) remains incompletely characterized. Notably, LOXL2 (a critical regulator of ECM stiffness) and SYVN1 (a key mediator of endoplasmic reticulum-associated degradation (ERAD)) may collaboratively promote metastatic transition through the ECM-endoplasmic reticulum stress (ERS)-ERAD axis.

[METHODS] TCGA-LIHC datasets were analyzed to evaluate LOXL2 and SYVN1 expression, single-gene survival correlations and dual-gene subgroup survival analysis in LIHC. Co-expressed genes were identified and subsequently subjected to functional enrichment analysis (Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG)) and protein-protein interaction (PPI) network construction. A dual-gene RiskScore model was constructed via multivariate Cox regression. Functional assays (CCK-8 proliferation, scratch wound healing) were performed in LIHC cell lines with LOXL2 or SYVN1 knockdown.

[RESULTS] LOXL2 was upregulated in LIHC and predicted reduced overall survival (OS) (p < 0.001), while low SYVN1 trended toward worse prognosis (p = 0.23). Dual high LOXL2/SYVN1 expression significantly correlated with reduced survival (p = 0.03). The RiskScore model confirmed high-risk patients had worse outcomes (HR = 1.76, p < 0.01). LOXL2 knockdown suppressed migration but increased proliferation; SYVN1 knockdown similarly altered metastatic phenotypes. Functional enrichment and PPI analyses supported their cooperative roles in LIHC progression.

[CONCLUSIONS] The functional interplay between LOXL2 and SYVN1 drives LIHC progression through the ECM-ERS-ERAD regulatory axis, and dual targeting of this axis may represent a potential therapeutic strategy.