In various tumor types, cell division cycle-associated 7 (CDCA7) is involved in chromatin remodeling and DNA methylation. However, its biological functions and regulatory mechanisms in gastric cancer (GC) remain unknown. This investigation intended to identify the function of CDCA7 in GC progression and elucidate its epigenetic regulatory mechanisms.

Differentially expressed genes (DEGs) were detected from the GSE19826, TCGA-GC, and GSE56807 datasets. Networks of protein-protein interactions (PPI) and hub genes were discovered by the DMNC and Clustering Coefficient algorithms. Receiver operating characteristic (ROC) analysis and expression profiling were undertaken to determine diagnostic performance. In vitro assays, including CCK-8 assays, clonogenic assays, flow cytometry, dot blots, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and Western blots, were applied to evaluate the role of CDCA7 and its interaction with helicase, lymphoid-specific (HELLS).

169 overlapping genes were discovered, enriched in Cell adhesion molecules and ECM-receptor interaction. CDCA7 is highly expressed in GC and has high clinical diagnostic value. Knockdown of CDCA7 causes apoptosis and suppresses GC cell invasion, migration, and proliferation. Mechanistically, CDCA7 physically interacts with HELLS and promotes HELLS recruitment to chromatin. Knockdown of CDCA7 reduces global 5 hmC/5 mC levels and histone methylation (H3K9me3 and H4K20me3), while HELLS overexpression partially reverses these effects. Functionally, HELLS overexpression also partially reverses the antiproliferative and proapoptotic effects of CDCA7 knockdown.

CDCA7 promotes GC progression by interacting with HELLS to regulate DNA methylation and chromatin stability, suggesting that the CDCA7-HELLS axis may serve as a potential diagnostic biomarker and therapeutic target for GC.

Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation, which has been linked to tumor progression and therapeutic resistance. However, the contribution of lactate metabolism and its receptor, hydroxycarboxylic acid receptor 1 (HCAR1), in ferroptosis regulation in gastric cancer (GC) remains poorly understood. Focusing specifically on its effects on cell proliferation, ferroptosis regulation, and the disruption of lactate-mediated metabolic pathways, the study aimed to clarify the role of HCAR1 in GC progression.

Bioinformatics analysis identified prognostic genes associated with ferroptosis in GC. Receiver operating characteristic (ROC) curves were generated to assess the diagnostic potential of the predictive genes. The biological role of HCAR1 was investigated through gain and loss-of-function experiments in GC cell lines, followed by assessments of cell viability, oxidative stress indicators, gene/protein expression, and ferroptosis sensitivity under lactate stimulation or HCAR1 modulation.

HCAR1 was significantly upregulated in GC tissues and linked to poor patient outcomes. Silencing HCAR1 inhibited GC cell growth and induced ferroptosis, as shown by increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA), along with decreased expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). Conversely, HCAR1 overexpression or exposure to extracellular lactate inhibited ferroptosis and activated antioxidant defenses. Mechanistically, lactate activation of HCAR1 increases ATP levels, which in turn inactivates AMP-activated protein kinase (AMPK). It also upregulates stearoyl-CoA desaturase 1 (SCD1) through the sterol regulatory element binding protein 1 (SREBP1) signaling pathway. Blocking HCAR1 reversed these effects and restored ferroptosis sensitivity.

HCAR1 mediates lactate-driven ferroptosis resistance in GC through the AMPK-SCD1 signaling pathway. Targeting the HCAR1-lactate axis may offer a promising strategy for overcoming metabolic adaptation and improving GC treatment outcomes.