Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41235254", "kind": "science-record", "revision": 4, "content_hash": "sha256:881419540f895970f36842b0b39a689030e1efaa20c8f430214eb772c59ca89c", "created_at": "2026-11-01T20:31:16Z", "updated_at": "2026-11-01T22:57:28Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Knockdown of TOP2A reverses cisplatin resistance in ovarian cancer by inhibiting EMT via ferroptosis mediated by the TP53/GPX4/SLC7A11 axis.", "doi": "10.3389/fimmu.2025.1675373", "pmid": "41235254", "authors": ["Xinyue Liu", "Junxia Wang", "Yangyu Liu", "Yan Han", "Zhichao Qin", "Yu Wang", "Shanxiang Gao", "Xinghua Li", "Yuping Suo"], "journal": "Frontiers in immunology", "year": 2025, "abstract": "Introduction: Cisplatin resistance is a major challenge in ovarian cancer therapy, particularly for high-grade serous ovarian cancer (HGSOC). DNA topoisomerase IIα (TOP2A) relates to cancer drug resistance, yet its role and molecular mechanisms in ovarian cancer cisplatin resistance remain unclear.\nMethods: TOP2A expression was detected in HGSOC tissues and cisplatin-resistant cells (SKOV3-DDP, OVCAR3-DDP). Functional assays combined with TOP2A knockdown evaluated cisplatin sensitivity and malignant phenotypes (proliferation, invasion, migration) in resistant cells. RNA-seq and GEO cisplatin resistance dataset (GSE214302) validated TOP2A's role in cisplatin resistance, prognostic value, and associations with TP53, GPX4, SLC7A11. Molecular docking/Co-IP confirmed TOP2A-TP53 interaction. Fer-1 and TP53 knockdown clarified TP53/GPX4/SLC7A11 axis regulation of ferroptosis and EMT, and an in vivo xenograft tumor model validated these findings.\nResults: TOP2A is highly expressed in HGSOC tissues and cisplatin-resistant cells, with high levels strongly associated with tumor progression (advanced stage, high grade, lymph node metastasis) and poor prognosis. RNA-seq shows TOP2A correlates with TP53, GPX4, SLC7A11.GEO dataset analysis confirms all four associate with cisplatin resistance. SLC7A11 and TOP2A are effective resistance biomarkers, and high TOP2A predicts shorter progression-free survival. Molecular assays verify direct TOP2A-TP53 interaction. Functional experiments reveal TOP2A knockdown enhances cisplatin sensitivity, inhibits malignancy, activates ferroptosis, and suppresses EMT via the TP53/GPX4/SLC7A11 axis. This effect is reversed by Fer-1 or TP53 knockdown, with mechanisms validated in vivo.\nConclusion: TOP2A represents a potential prognostic biomarker and therapeutic target for cisplatin resistance in ovarian cancer (OC), as it regulates ferroptosis and EMT via the TP53/GPX4/SLC7A11 axis, which is mediated by its direct interaction with TP53. This thus provides a novel direction for treating cisplatin-resistant OC.", "claims": [{"id": "claim-method", "statement": "Differences between groups were evaluated using Student’s t-test and chi-square (χ²) test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41235254", "locator": "sections[20] \"Statistical analysis\" paragraph 2", "quote": "Differences between groups were evaluated using Student’s t-test and chi-square (χ²) test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The original contributions presented in the study are publicly available. This data can be found here: http://www.ncbi.nlm.nih.gov/bioproject/1314868 (BioProject ID: PRJNA1314868).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41235254", "locator": "sections[34] \"Data availability statement\" paragraph 2", "quote": "The original contributions presented in the study are publicly available. This data can be found here: http://www.ncbi.nlm.nih.gov/bioproject/1314868 (BioProject ID: PRJNA1314868)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Analysis of RNA-seq and GEO dataset GSE214302 showed that high TOP2A expression is associated with cisplatin resistance and shorter progression-free survival in ovarian cancer.", "kind": "quantitative", "target": {"value": 0.7, "unit": "auc", "tolerance": null, "source": "TOP2A showed moderate diagnostic efficacy (AUC = 0.700)."}, "evidence": [{"asset": "source:pmid:41235254", "locator": "sections[13] \"Bioinformatics analysis\" paragraph 2", "quote": "Sequencing data from the GSE214302 microarray were downloaded from the GEO database."}, {"asset": "source:pmid:41235254", "locator": "sections[25] \"The TOP2A-TP53-ferroptosis axis synergistically regulates cisplatin resistance and prognosis in OC\" paragraph 2", "quote": "TOP2A showed moderate diagnostic efficacy (AUC = 0.700)."}, {"asset": "source:pmid:41235254", "locator": "sections[25] \"The TOP2A-TP53-ferroptosis axis synergistically regulates cisplatin resistance and prognosis in OC\" paragraph 2", "quote": "This suggests a close correlation between high TOP2A expression and shorter PFS in ovarian cancer patients."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "Analysis of RNA-seq and GEO dataset GSE214302 showed that high TOP2A expression is associated with cisplatin resistance and shorter progression-free survival in ovarian cancer.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:41235254"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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Functional assays combined with TOP2A knockdown evaluated cisplatin sensitivity and malignan", "irmed TOP2A-TP53 interaction. Fer-1 and TP53 knockdown clarified TP53/GPX4/SLC7A11 axis regulation", "raction. Functional experiments reveal TOP2A knockdown enhances cisplatin sensitivity, inhibits mal"], "order_basis": "paper_text_order:0", "id": "assay:1"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["on, invasion, migration) in resistant cells. RNA-seq and GEO cisplatin resistance dataset (GSE214", ", lymph node metastasis) and poor prognosis. 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