Time-Resolved Transcriptomic Profiling of Surgical Wounds Identifies Stage-Specific Therapeutic Targets for Residual...

Background: The optimal timing of adjuvant chemotherapy after cytoreductive surgery in epithelial ovarian cancer remains uncertain, and perioperative wound-healing responses may transiently create a pro-tumorigenic and drug-resistant microenvironment. This study aimed to characterize time-dependent wound-induced transcriptomic alterations and to identify pharmacologic agents capable of reversing these responses. Methods: An ID8 murine ovarian cancer model was used to compare no treatment, anesthesia alone, and anesthesia plus surgical wounding mimicking futile laparotomy. Tumors were collected at baseline, 1 day (T1), 1 week (T2), and 2 weeks (T3) after intervention. RNA sequencing was performed, and wound-specific differentially expressed genes (WsDEGs) were defined by excluding anesthesia- and progression-related signatures. Functional enrichment analyses were conducted, followed by transcriptome-based drug repurposing using the REMEDY platform to identify compounds predicted to reverse wound-induced gene expression profiles. Results: Surgical wounding significantly increased tumor burden at T1. Transcriptomic analyses revealed distinct, time-dependent wound-associated programs. At T1, WsDEGs were enriched in inflammatory signaling, coagulation, angiogenesis, and immune cell migration, with Vorinostat and Homoharringtonine identified as top candidates to counteract these signatures. At T2, pathways related to cell survival, adhesion, and morphogenesis predominated, with LY-2090314, Artesunate, and Birinapant emerging as potential modulators. At T3, cell-cycle regulation and lipid metabolic pathways were dominant, and Fulvestrant, Atorvastatin, Imatinib, and ABT-737 were predicted to inhibit these processes. Conclusions: Perioperative surgical wounding induces dynamic, stage-specific transcriptomic programs that may promote ovarian cancer progression and alter drug responsiveness. These findings support time-adapted perioperative pharmacologic strategies to optimize postoperative cancer therapy.