PAQR5 links microvascular invasion, innate immune inflammatory amplification, and platinum resistance in ovarian cancer

BACKGROUND: Platinum resistance remains the principal obstacle to improving survival in ovarian cancer. Microvascular invasion (MVI) is associated with chemoresistance and immune remodeling, but the molecular regulators connecting vascular invasion, innate immune-driven inflammatory amplification, and treatment failure remain poorly defined. METHODS: Three public datasets and 118 literature-curated MVI genes were integrated. Differential expression analysis followed by three-way intersection identified PAQR5 as the core candidate. Its clinical, immune-inflammatory, and pharmacological relevance was mapped using CIBERSORT, ESTIMATE, pRRophetic, and nomogram modeling, and validated by qPCR/Western blot, MTT/CCK-8, colony/wound-healing assays, flow cytometry, gamma-H2AX foci, EdU incorporation, and subcutaneous xenografts (n = 5-6 mice/group). RESULTS: PAQR5 was the only gene shared among cisplatin-resistance signatures in vitro (303 DEGs), patient tissue resistance signatures (2507 DEGs), and the MVI gene set. TCGA tumors overexpressed PAQR5 2.8-fold compared with GTEx normal tissue (P < 0.001). High PAQR5 independently predicted shortened overall survival (HR = 1.18; 95% CI 1.02-1.44; P = 0.005) and 5-year progression-free survival (HR = 1.33; 95% CI 1.09-1.63; P = 0.04). In silico, PAQR5-high tumors showed an innate immune-skewed suppressive profile, with increased M2 macrophages (+28%) and Tregs (+17%) but reduced CD8+ T cells (-31%) and NK cells (-21%; all P < 0.01). They also displayed elevated cisplatin, docetaxel, and paclitaxel IC50 values (each P < 0.0001), whereas AKT-inhibitor VIII IC50 fell 1.7-fold. Functionally, PAQR5 overexpression increased proliferation, colony formation, migration, DNA damage tolerance, and xenograft growth, whereas silencing produced mirror-image suppression and restored cisplatin-induced apoptosis. CONCLUSION: PAQR5 appears to couple MVI with platinum resistance by coordinating an immunosuppressive inflammatory tumor microenvironment, enhanced DNA damage repair, and reduced apoptosis. These findings nominate PAQR5 as a mechanism-linked biomarker and a therapeutic entry point for targeting inflammation-associated chemoresistance in ovarian cancer.