Unveiling hypoxic regulatory networks by bioinformatics: mechanisms of hypoxia-related hub genes driving rituximab resistance and poor prognosis in DLBCL.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41189944", "kind": "science-record", "revision": 3, "content_hash": "sha256:a1ddfef3062db9b739fcaa7e217f88aed21a9da13a00197c9a66184d6d5c0084", "created_at": "2026-11-01T20:31:13Z", "updated_at": "2026-11-01T22:14:56Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Unveiling hypoxic regulatory networks by bioinformatics: mechanisms of hypoxia-related hub genes driving rituximab resistance and poor prognosis in DLBCL.", "doi": "10.3389/fonc.2025.1592441", "pmid": "41189944", "authors": ["Jiayi Yao", "Juan Huang", "Yuanfei Mao", "Zizhen Xu"], "journal": "Frontiers in oncology", "year": 2025, "abstract": "Background: Diffuse large B-cell lymphoma (DLBCL), an aggressive subtype of non-Hodgkin lymphoma, exhibits heterogeneous clinical outcomes. While rituximab, a CD20 inhibitor, combined with chemotherapy has improved survival in some patients, resistance remains prevalent, particularly in hypoxic tumor microenvironments. Understanding hypoxia-related genes (HRGs) and their role in rituximab resistance is critical to addressing therapeutic challenges in high-risk DLBCL.\nMethods: Gene expression profiles from GEO datasets (GSE56315: DLBCL tumor vs. normal; GSE104212: hypoxia-treated DLBCL cell lines) were analyzed to identify overlapping genes between DLBCL-signature genes (DSGs) and HRGs. protein interaction network topology analysis and Lasso regression modeling of TCGA-DLBC dataset were employed to screen regulator and hub genes. Hub genes linked to rituximab response and survival were validated in DLBCL patients receiving rituximab therapy. Functional enrichment analysis was used to explore associated pathways. The expression of the identified regulator and hub genes was validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR).\nResults: 58 overlapping genes were identified between DSGs and HRGs. PPI network and Lasso regression revealed 5 MS4A1 regulator genes and 10 hub genes. Among these, LGALS1 (HR = 0.588, p = 0.00085), TIMP1 (HR = 0.591, p = 0.00098), ANXA1 (HR = 0.614, p=0.0024) and STAP1 (HR = 0.633, p=0.0035) were significantly associated with overall survival and GPNMB (AUC = 0.869), CDCA7 (AUC = 0.686), and STAP1 (AUC = 0.663) associated with treatment response in rituximab-treated patients. Functional analysis implicated these genes in B-cell receptor (BCR) and PI3K-AKT signaling pathways, suggesting their mechanistic roles in therapeutic resistance.\nConclusions: This study identifies hypoxia-associated genes critical to rituximab resistance in DLBCL, highlighting potential therapeutic targets. Their involvement in BCR and PI3K-AKT pathways underscores novel vulnerabilities for overcoming refractory disease. Our findings provide a foundation for developing strategies to improve outcomes in high-risk DLBCL patients with hypoxic microenvironments.", "claims": [{"id": "claim-method", "statement": "Transcriptome-wide differential expression analysis was systematically conducted according to fold change (FC) and t-test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41189944", "locator": "sections[4] \"Identification of differential expression genes\" paragraph 2", "quote": "Transcriptome-wide differential expression analysis was systematically conducted according to fold change (FC) and t-test."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Publicly available datasets were analyzed in this study. This data can be found here: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE10846 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE56315 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104212.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41189944", "locator": "sections[21] \"Data availability statement\" paragraph 2", "quote": "Publicly available datasets were analyzed in this study. This data can be found here: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE10846 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE56315 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104212."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The study identified 58 overlapping genes between DLBCL-signature genes and hypoxia-related genes.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41189944", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "58 overlapping genes were identified between DSGs and HRGs."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The study identified 58 overlapping genes between DLBCL-signature genes and hypoxia-related genes.", "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:41189944"], "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:GSE104212"], "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:GSE104212"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:41189944", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fonc.2025.1592441", "sha256": "sha256:b36f22b4eafca0430abf0bf8e0f24868c9e75018badaf13c33bbbf6943df554c", "bytes": 39581, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fonc.2025.1592441", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12580093", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE104212", "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=GSE104212", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE104212", "version": null, "note": "Publicly available datasets were analyzed in this study. 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No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["survival_km"], "assets": ["source:pmid:41189944", "data:geo:GSE104212"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE104212"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T20:04:50Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 10802, "completion_tokens": 1611, "cached_tokens": 256}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:41189944", "type": "paper", "label": "pmid:41189944"}, {"id": "source:pmid:41189944", "type": "manuscript", "label": "PMID 41189944 full text"}, {"id": "data:geo:GSE104212", "type": "dataset", "label": "GEO GSE104212"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:41189944", "type": "paper", "label": "pmid:41189944"}, {"id": "source:pmid:41189944", "type": "manuscript", "label": "PMID 41189944 full text"}, {"id": "data:geo:GSE104212", "type": "dataset", "label": "GEO GSE104212"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-41189944", "type": "extraction", "used": ["source:pmid:41189944"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE104212", "type": "accession_resolution", "used": ["data:geo:GSE104212"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:41189944", "parent_hash": "sha256:20f3fdbdf0c8d3c6fdb8319e1e2a4f8feb5f17ce7d35fe8184b00cce05aa9394", "fork_of": null, "generation": 2}, "gaps": ["asset:data:geo:GSE104212 licence not read", "asset:data:geo:GSE104212 not downloaded", "asset:data:geo:GSE10846 licence not read", "asset:data:geo:GSE10846 not downloaded", "asset:data:geo:GSE56315 licence not read", "asset:data:geo:GSE56315 not downloaded", "execution.not_run", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["tion quantitative polymerase chain reaction (RT-qPCR). Results: 58 overlapping genes were identif", "n quantitative polymerase chain reaction (RT-qPCR). Results: 58 overlapping genes were identif", "tion quantitative polymerase chain reaction (RT-qPCR) analysis on the 6 genes with clinical signi", "n quantitative polymerase chain reaction (RT-qPCR) analysis on the 6 genes with clinical signi"], "order_basis": "paper_text_order:1276", "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": ["iao Tong University in Shanghai, China, were cultured in RPMI-1640 medium (Gibco, USA) supplemented w"], "order_basis": "paper_text_order:4018", "id": "assay:2"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["survival_km"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Kaplan-Meier"], "order_basis": "consumes_earlier_output", "id": "assay:3"}]}