Analysis and Validation of Differentially Expressed Ferroptosis-Related Genes in Regorafenib-Induced Cardiotoxicity.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:36204517", "kind": "science-record", "revision": 5, "content_hash": "sha256:585f6ff71264d82c2107d0218a5a3185c2f2bd6e3c691221694545af68b8c58a", "created_at": "2026-11-01T18:15:31Z", "updated_at": "2026-11-01T22:50:15Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Analysis and Validation of Differentially Expressed Ferroptosis-Related Genes in Regorafenib-Induced Cardiotoxicity.", "doi": "10.1155/2022/2513263", "pmid": "36204517", "authors": ["Siyuan Zhang", "Xueming Xu", "Zhangyi Li", "Tian Yi", "Jingyu Ma", "Yan Zhang", "Yilan Li"], "journal": "Oxidative medicine and cellular longevity", "year": 2022, "abstract": "Background: Although tyrosine kinase inhibitors (TKIs) constitute a type of anticancer drugs, the underlying mechanisms of TKI-associated cardiotoxicity remain largely unknown. Ferroptosis is a regulated cell death form that implicated in several tumors' biological processes. Our objective was to probe into the differential expression of ferroptosis-related genes in regorafenib-induced cardiotoxicity through multiple bioinformatics analysis and validation.\nMethods and Materials: Four adult human cardiomyocyte cell lines treated with regorafenib were profiled using Gene Expression Omnibus (GEO) (GSE146096). Differentially expressed genes (DEGs) were identified using DESeq2 in R (V.3.6.3). Then, Gene Ontology (GO) Enrichment Analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment Analysis, and Gene Set Enrichment Analysis (GSEA) were used to explore DEGs' bioinformatics functions and enriched pathways. We intersected DEGs with 259 ferroptosis-related genes from the FerrDb database. Finally, the mRNA levels of differentially expressed ferroptosis-related genes (DEFRGs) were validated in regorafenib-cultured cardiomyocytes to anticipate the link between DEFRGs and cardiotoxicity.\nResults: 747,1127,773 and 969 DEGs were screened out in adult human cardiomyocyte lines A, B, D, and E, respectively. The mechanism by which REG promotes cardiotoxicity associated with ferroptosis may be regulated by PI3K-Akt, TGF-beta, and MAPK. GSEA demonstrated that REG can promote cardiotoxicity by suppressing genes and pathways encoding extracellular matrix and related proteins, oxidative phosphorylation, or ATF-2 transcription factor network. After overlapping DEGs with ferroptosis-related genes, we got seven DEFRGs and found that ATF3, MT1G, and PLIN2 were upregulated and DDIT4 was downregulated. The ROC curve demonstrated that these genes predict regorafenib-induced cardiotoxicity well.\nConclusion: We identified four DEFRGs which may become potential predictors and participate in the regorafenib-induced cardiotoxicity. Our findings provide possibility that targeting these ferroptosis-related genes may be an alternative for clinical prevention and therapy of regorafenib-related cardiotoxicity.", "claims": [{"id": "claim-method", "statement": "To obtain DEGs that may cause cardiotoxicity with the anticancer drug REG, we, respectively, performed differential expression analysis of four groups of adult heart-derived primary cardiomyocytes from GSE146096 dataset using the DESeq2 R package [21].", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36204517", "locator": "sections[13] \"3.1. Identification of Differentially Expressed Genes\" paragraph 2", "quote": "To obtain DEGs that may cause cardiotoxicity with the anticancer drug REG, we, respectively, performed differential expression analysis of four groups of adult heart-derived primary cardiomyocytes from GSE146096 dataset using the DESeq2 R package [21]."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Publicly available datasets were analyzed in this study. The mRNA expression profiles were obtained from the GEO databases (https://www.ncbi.nlm.nih.gov/gds/), namely, GSE146096.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:36204517", "locator": "sections[22] \"Data Availability\" paragraph 2", "quote": "Publicly available datasets were analyzed in this study. The mRNA expression profiles were obtained from the GEO databases (https://www.ncbi.nlm.nih.gov/gds/), namely, GSE146096."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Differential-expression analysis identified 747, 1127, 773, and 969 DEGs in cardiomyocyte lines A, B, D, and E, respectively.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:36204517", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "747,1127,773 and 969 DEGs were screened out in adult human cardiomyocyte lines A, B, D, and E, respectively."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Differential-expression analysis identified 747, 1127, 773, and 969 DEGs in cardiomyocyte lines A, B, D, and E, respectively.", "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:36204517"], "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. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE146096"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE146096"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:36204517", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1155/2022/2513263", "sha256": "sha256:408736fdcd901084aa759f56690852f8b1f260a9087bcf6355cb0f03aa23a1ba", "bytes": 48645, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1155/2022/2513263", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC9530921", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE146096", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE146096", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE146096", "version": null, "note": "Publicly available datasets were analyzed in this study. The mRNA expression profiles were obtained from the GEO databases (https://www.ncbi.nlm.nih.gov/gds/), namely, GSE146096.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Publicly available datasets were analyzed in this study. 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Supplem", "order to verify the above 7 DEGs, real time-qPCR and statistical analysis were performed on c", "(f), and PLIN2 (g) was measured by real time-qPCR. ∗P < 0.05; ∗∗P < 0.01, ∗∗∗P < 0.001 vs. con", "emental Table 1: the primer sequences for RT-qPCR.Click here for additional data file. Supplem"], "order_basis": "paper_text_order:4869", "id": "assay:1"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["R and statistical analysis were performed on cultured cells, the specific results were shown in Fi"], "order_basis": "paper_text_order:4916", "id": "assay:2"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["To obtain DEGs that may cause cardiotoxicity with the anticancer drug REG, we, respectively, performed differential expression analysis of four groups of adult heart-derived primary cardiomyocytes from GSE146096 dataset using the DESeq2 R package [21]."], "order_basis": "consumes_earlier_output", "id": "assay:3"}]}