Two cycles of chemotherapy modulate itaconic acid levels via ATF3/TET2/NF-κB pathways in ovarian cancer among Han Chinese women

The metabolic rationale chemotherapy cycles after debulking surgery in ovarian cancer (OC) remain unclear. This prospective cohort was aimed to define metabolic changes induced by chemotherapy and assess longitudinal effects. Metabolites between treatment-naïve OC patients (n = 26) and age-matched healthy controls (n = 30) were identified by gas chromatography-mass spectrometry (GC-MS). Chemotherapy-related signaling molecules were quantified via enzyme-linked immunosorbent assay. Our analysis identified 38 differentially expressed metabolites, including critical intermediates in the tricarboxylic acid (TCA) cycle and revealed significant reductions in five TCA cycle intermediates, namely itaconic acid, citric acid, fumaric acid, cis-aconitic acid, and malic acid, in OC patients compared to controls. Following the first chemotherapy cycle, absolute quantification of 128 metabolites was performed, with targeted metabolomic analysis of TCA cycle intermediates revealing an increase in levels of itaconic acid prior to the second chemotherapy cycle. Remarkably, after two chemotherapy cycles, itaconic acid concentrations normalized to levels comparable to those in healthy controls, suggesting metabolic recovery. Furthermore, significant inverse correlations were observed between human epididymis protein 4 (HE4) levels and the concentrations of the five TCA cycle intermediates, highlighting the potential of these metabolites as biomarkers. Mechanistic studies revealed that two cycles of chemotherapy restored metabolic homeostasis, normalizing itaconic acid levels and reactivating the Activating transcription factor 3 (ATF3)/ten-eleven translocation 2 (TET2)/NF-kappaB (NF-κB) signaling pathway to levels seen in healthy participants. Our pilot data suggest that two chemotherapy cycles may help restore metabolic homeostasis in patients who have undergone complete cytoreduction. These findings provide preliminary insights into chemotherapy-induced metabolic reprogramming and warrant further investigation in larger, outcome-driven studies. ClinicalTrials.gov ID: ChiCTR2300069160.