The revelation of UCHL1 in malignant epithelial cells of TNBC reinforcing cisplatin resistance by modulating ferroptosis based on single-cell transcriptome data.

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Single-cell RNA sequencing (scRNA-seq) plays a pivotal part in revealing the mechanism of drug resistance in tumors. This work aimed to explore the molecular events driving TNBC resistance based on scRNA-seq data. Breast cancer (BC) scRNA-seq data GSE176078 was sourced from the GEO database. Nine TNBC samples were analyzed. The cellular composition and differentially expressed genes of TNBC were clarified through dimension reduction, clustering, and cell annotation. Drug-resistant and sensitive epithelial cell clusters in malignant epithelial cells were identified, with their heterogeneity analyzed. Key genes driving drug-resistant epithelium were screened and KEGG enrichment analysis was undertaken. The expression of Ubiquitin Carboxy-Terminal Hydrolase L1 (UCHL1) in TNBC was examined. The effect and molecular mechanism of UCHL1 on cisplatin (CDDP) resistance in TNBC was confirmed by constructing CDDP-resistant cell lines. We successfully identified resistant and sensitive cell clusters in malignant epithelial cells of TNBC and screened for the greatly upregulated gene UCHL1 in the resistant epithelium. KEGG analysis revealed its enrichment in the ferroptosis signaling pathway. Further analyses demonstrated the upregulation of UCHL1 in CDDP-resistant TNBC cells. Knocking down UCHL1 potentiated the sensitivity of TNBC cells to CDDP treatment and reinforced ferroptosis. The ferroptosis inhibitor Ferrostatin-1 reversed the inhibitory effect of UCHL1 knockdown on CDDP resistance. UCHL1 reinforces CDDP resistance in TNBC by suppressing ferroptosis. The study brings new insights into the drug-resistance mechanism of TNBC.", "claims": [{"id": "claim-method", "statement": "Student’s t test was employed for comparing differences between the two groups, and a one-way analysis of variance was for comparing differences between multiple groups.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40777820", "locator": "sections[17] \"Statistical analysis\" paragraph 2", "quote": "Student’s t test was employed for comparing differences between the two groups, and a one-way analysis of variance was for comparing differences between multiple groups."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The data and materials in the current study are available from the corresponding author on reasonable request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40777820", "locator": "sections[28] \"Availability of Data and Materials\" paragraph 2", "quote": "The data and materials in the current study are available from the corresponding author on reasonable request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "UCHL1 reinforces CDDP resistance in TNBC by suppressing ferroptosis.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40777820", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "UCHL1 reinforces CDDP resistance in TNBC by suppressing ferroptosis."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "UCHL1 reinforces CDDP resistance in TNBC by suppressing ferroptosis.", "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:40777820"], "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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