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IntroductionHepatocellular carcinoma (HCC) is characterized by a complex tumor microenvironment and limited therapeutic options. Synaptogyrin-2 (SYNGR2), a transmembrane protein, has been implicated in cancer but its comprehensive role in HCC prognosis, immune regulation, and treatment response remains unclear.MethodsMultiomics bioinformatics analysis was performed via RNA-seq data from the TCGA-LIHC cohort. Prognostic value was assessed via Cox regression and Kaplan‒Meier analysis. Immune cell infiltration was estimated via CIBERSORT, and drug sensitivity was predicted via the oncoPredict R package. In vitro validation was conducted using Hep3B and Huh7 cell lines. To establish causality, isogenic gain- and loss-of-function experiments were performed, followed by RT-qPCR, and CCK-8 assays.ResultsSYNGR2 expression was significantly elevated in HCC tissues and correlated with advanced tumor stage, poor differentiation, and poor overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (all P<0.05). It served as an independent prognostic biomarker (AUC=0.923). High SYNGR2 expression was associated with an immunosuppressive microenvironment characterized by increased numbers of M0 macrophages and Tregs and strongly positively correlated with immune checkpoint genes (PD-1, CTLA-4, and PD-L1). Bioinformatic predictions revealed that SYNGR2-high tumors were more sensitive to MK-1775 (DNA damage inhibitor) and paclitaxel, whereas SYNGR2-low tumors were sensitive to JAK1/IAP inhibitors. In vitro, Hep3B cells (high endogenous SYNGR2) displayed a markedly lower IC50 for MK-1775 than Huh7 cells (low endogenous SYNGR2). Critically, plasmid-mediated overexpression of SYNGR2 in Huh7 cells significantly sensitized them to MK-1775, while siRNA-mediated knockdown of SYNGR2 in Hep3B cells conferred significant resistance, establishing a causal role for SYNGR2 in modulating sensitivity to this WEE1 inhibitor.ConclusionSYNGR2 has emerged as a multifaceted biomarker candidate in HCC, associated with prognosis, an immunosuppressive microenvironment, and differential therapeutic responses. Its integration into clinical models could enhance prognostic stratification and guide personalized treatment strategies, particularly in selecting patients for DNA damage-targeting agents.