PRDX4 Activates the Dual Enzymatic Functions of IRE1α to Promote Ovarian Cancer Progression

Background Ovarian cancer is recognized as the most lethal gynecological malignancy, with high-grade serous carcinoma (HGSC) being the most prevalent and aggressive subtype. Due to the absence of typical early symptoms, the majority of patients are diagnosed at advanced stages, and effective biomarkers for early detection and prognosis remain elusive. Peroxiredoxin 4 (PRDX4), a cysteine-dependent peroxidase uniquely localized to the endoplasmic reticulum, has been implicated in protein folding and cellular homeostasis. However, its role in the progression of ovarian cancer has not been systematically investigated. This study aims to elucidate the expression patterns, biological functions, and molecular mechanisms of PRDX4 in HGSC. Methods: Transcriptomic and proteomic data from TCGA, GTEx, CPTAC, and an independent HGSC cohort were integrated to analyze PRDX4 expression and its clinical correlations. Immunohistochemistry was performed on patient tissues to validate PRDX4 expression. Functional assays, including proliferation, colony formation, apoptosis, migration, invasion, and xenograft tumor growth, were conducted in PRDX4 overexpression and knockdown cell models. Correlation analyses and molecular experiments were utilized to investigate the interaction between PRDX4 and the IRE1α pathway, with pharmacological inhibition applied to confirm functional relevance. Results Multi-omics analyses revealed that PRDX4 is significantly upregulated in ovarian cancer tissues, correlating with an increased likelihood of receiving hyperthermic intraperitoneal chemotherapy (HIPEC) and poorer overall survival outcomes. Immunohistochemistry further validated the overexpression of PRDX4 in HGSC specimens, which was associated with advanced FIGO stage. Functional assays demonstrated that PRDX4 promotes proliferation, migration, invasion, and tumor growth, whereas its knockdown suppressed these malignant phenotypes and induced apoptosis. Mechanistically, PRDX4 activates both enzymatic functions of IRE1α, facilitating XBP1s splicing and JNK–c-JUN signaling pathways. Pharmacological inhibition of IRE1α using Kira6 effectively abrogated PRDX4-driven proliferation and survival, confirming the reliance of PRDX4-mediated tumor progression on IRE1α activity. Conclusions PRDX4 is markedly overexpressed in ovarian cancer and is linked to adverse clinicopathological features and poor prognosis. By activating the dual functions of IRE1α, PRDX4 enhances tumor cell survival and invasiveness, highlighting its potential as a biomarker and therapeutic target in ovarian cancer.