GINS complex couples DNA replication stress to therapeutic resistance in hepatocellular carcinoma

Table 1 GINS subunits in hepatocellular carcinoma: Evidence, mechanisms, and translational implications

Subunit	Evidence level	Current HCC evidence	Reported or proposed mechanisms	Translational implication	Main limitation
GINS1	Moderate	Functional and prognostic evidence in HCC	E2F1 activation; beta-catenin/ZEB1-mediated EMT; proliferation and stemness	Candidate marker for aggressive, stemness-enriched HCC	Direct evidence for therapy resistance remains limited
GINS2	Moderate	Functional evidence in HCC	E2F1-mediated transcriptional activation; PI3K/AKT/mTOR signaling	Candidate marker of proliferative and replication-active HCC	Role in drug resistance and immune response remains unclear
GINS3	Low/inferential	Mainly bioinformatic or association-based evidence	Methylation, expression association, possible immune escape; structural role in GINS tetramer	Hypothesis-generating biomarker	Lacks HCC-specific functional validation
GINS4	Moderate	Prognostic and functional evidence in HCC	Cell-cycle regulation; PI3K/AKT signaling; POLE2/ferroptosis-related axis	Candidate marker and potential replication-fork/ferroptosis-related node	Needs in vivo validation and therapeutic testing

HCC: Hepatocellular carcinoma; EMT: Epithelial-mesenchymal transition; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin.