Abstract / Summary
Cell Division Cycle-Associated 5 (CDCA5), also known as Sororin, is an essential regulator of sister chromatid cohesion and cell-cycle progression. Although CDCA5 has been implicated in several malignancies, its functional role in hepatocellular carcinoma (HCC), particularly in relation to ferroptosis and tumor-associated molecular features, remains incompletely understood. CDCA5 expression and clinical relevance were evaluated using transcriptomic sequencing of clinical HCC specimens, TCGA/GTEx datasets, and pan-cancer bioinformatic analyses. Associations between CDCA5 and genomic instability, DNA repair-related signatures, immune infiltration, alternative splicing, and ferroptosis-related genes were assessed using public multi-omics resources. The biological functions of CDCA5 in HCC were investigated through gain- and loss-of-function experiments, including CCK-8, EdU, colony formation, wound-healing, Transwell, cell-cycle, apoptosis, and xenograft assays. Ferroptosis was evaluated by cell-death rescue experiments, MDA, ROS, GSH, mitochondrial activity, iron measurements, and C11-BODIPY lipid peroxidation staining. Mechanistic studies included proteomic analysis, pharmacological and genetic perturbation of PP2Ac, p53 modulation, ChIP-qPCR, and dual-luciferase reporter assays. CDCA5 was significantly upregulated in HCC tissues and was associated with advanced clinicopathological features and unfavorable prognosis. Pan-cancer analyses revealed that CDCA5 expression correlated with genomic instability, DNA repair-related signatures, epigenetic features, immune infiltration patterns, and drug-response-related profiles, although these findings were primarily correlative. Functionally, CDCA5 knockdown suppressed HCC cell proliferation, migration, and invasion, induced G2/M arrest, and reduced xenograft tumor growth, whereas CDCA5 overexpression promoted malignant phenotypes. CDCA5 depletion increased ferroptosis-associated changes, including lipid peroxidation, ROS accumulation, GSH depletion, mitochondrial dysfunction, and Fe 2+ accumulation, while these effects were attenuated by ferroptosis inhibitors. Mechanistically, CDCA5 promoted PP2Ac expression, reduced p53 phosphorylation, and decreased p53-dependent STEAP3 transcription, thereby limiting ferroptotic sensitivity. Genetic and pharmacological modulation of PP2Ac and STEAP3 further supported this regulatory mechanism. This study identifies CDCA5 as a clinically relevant biomarker and functional promoter of HCC progression. Our findings suggest that CDCA5 contributes to ferroptosis resistance through a PP2Ac/p53/STEAP3-related regulatory mechanism, providing a potential therapeutic entry point for restoring ferroptotic vulnerability in HCC.