High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive form of epithelial ovarian cancer and is characterized by high recurrence rates and poor clinical outcomes. In this study, we identify molecular signatures associated with recurrence by conducting integrative transcriptomic and proteomic analyses on paired primary and recurrent HGSOC tissues from 34 patients. RNA sequencing and proteomic profiling revealed 185 differentially expressed genes (DEGs) and 36 differentially expressed proteins (DEPs) linked to recurrence. Pathway enrichment and Ingenuity pathway analyses highlighted the involvement of immune cell trafficking, cell signaling, and MAPK pathway activation in recurrent tumors. A survival analysis identified seven DEGs that correlated significantly with recurrence-free survival; among them, IL7R, IRF8, and PTPRC were upregulated in recurrent tumors and associated with poor prognosis, and NSG1 was downregulated and linked to favorable outcomes. Immunohistochemistry validated the differential expression of these markers at the protein level. The proteomic analysis demonstrated that recurrent tumor-specific DEGs are functionally linked to MAPK signaling. Co-expression analyses revealed dynamic regulatory interactions between the DEGs and DEPs, suggesting context-dependent molecular shifts during recurrence. This integrative multi-omics approach reveals that key molecular alterations underlie HGSOC recurrence and identifies IL7R, IRF8, PTPRC, and NSG1 as potential prognostic biomarkers and therapeutic targets. Our findings provide a foundation for targeted strategies to improve outcomes for patients with recurrent HGSOC.

Hypoxia and nutrient deprivation are fundamental drivers of tumor aggressiveness and therapeutic resistance in hepatocellular carcinoma (HCC). While the involvement of neural components in the tumor microenvironment (TME) is increasingly recognized, the molecular transducers linking metabolic stress to neuron–tumor crosstalk remain elusive. Here, we identify ADAM23 (A disintegrin and metalloproteinase 23) as a hypoxia‐responsive mediator that mediates communication between HCC cells and neuronal cells. ADAM23 expression was markedly upregulated in HCC cells under both chemical (CoCl ₂ ) and physical hypoxia (1% O ₂ ), a process further amplified by glucose deprivation and directly modulated by HIF‐1α. Functional assays revealed that ADAM23 overexpression promotes epithelial–mesenchymal transition (EMT) and enhances cell viability under metabolic stress. Notably, sorafenib‐resistant HCC cells (Huh7SR) exhibited high levels of ADAM23 secretion, which triggered proliferative and metabolic activation in neuronal SH‐SY5Y cells. In 3D co‐culture spheroid models, Huh7SR cells mixed with SH‐SY5Y cells displayed significantly larger spheroid volumes and enhanced neuronal fluorescence compared with parental controls, suggesting that ADAM23‐mediated interactions facilitate a supportive neural niche. Analysis of The Cancer Genome Atlas (TCGA) datasets and patient microarrays confirmed that ADAM23 is significantly overexpressed in HCC and positively correlates with HIF‐1α expression. Moreover, elevated expression of ADAM23 was significantly correlated with poor overall survival. Collectively, our findings underscore ADAM23 as a critical metabolic‐neural linker that promotes HCC progression and drug resistance. These findings suggest that the ADAM23‐mediated neuron–tumor axis may represent a potential therapeutic target in aggressive HCC.

High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive form of epithelial ovarian cancer, characterized by high recurrence rates and poor clinical outcomes. In this study, we identify molecular signatures associated with recurrence by conducting integrative transcriptomic and proteomic analyses on paired primary and recurrent HGSOC tissues from 34 patients. RNA sequencing and proteomic profiling revealed 185 differentially expressed genes (DEGs) and 36 differentially expressed proteins (DEPs) linked to recurrence. Pathway Enrichment and Ingenuity Pathway Analysis highlighted the involvement of immune cell trafficking, cell signaling, and MAPK pathway activation in recurrent tumors. Survival analysis identified seven DEGs significantly correlated with recurrence-free survival; among these, IL7R, IRF8, and PTPRC were upregulated in recurrent tumors and associated with poor prognosis, while NSG1 was downregulated and linked to favorable outcomes. Immunohistochemistry validated the differential expression of these markers at the protein level. Proteomic analysis demonstrated that recurrent tumor-specific DEGs are functionally linked to MAPK signaling. Co-expression analyses revealed dynamic regulatory interactions between DEGs and DEPs, suggesting context-dependent molecular shifts during recurrence. This integrative multi-omics approach reveals key molecular alterations underlying HGSOC recurrence and identifies IL7R, IRF8, PTPRC, and NSG1 as potential prognostic biomarkers and therapeutic targets. Our findings provide a foundation for targeted strategies to improve outcomes for patients with recurrent HGSOC.