Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:33425905", "kind": "science-record", "revision": 7, "content_hash": "sha256:368e95082ab69f3f29c9db7cc4b2ae1723b6e541fd4373a86c01aef5e1335455", "created_at": "2026-11-01T15:41:22Z", "updated_at": "2026-11-01T22:02:55Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma.", "doi": "10.3389/fcell.2020.596679", "pmid": "33425905", "authors": ["Yang Liu", "Xi Zhang", "Junjun Zhang", "Juan Tan", "Jie Li", "Zewen Song"], "journal": "Frontiers in cell and developmental biology", "year": 2020, "abstract": "BACKGROUND: Immunotherapy and sorafenib exert anti-tumor effects via ferroptosis, but reliable biomarkers for the individual treatment and prognosis prediction of hepatocellular carcinoma (HCC) based on the ferroptosis and immune status remain lacking.\nMETHODS: Ferroptosis-related genes (FRGs) were identified by downloading data from FerrDb and by searching and reading original articles from PubMed. Immune-related genes (IRGs) were downloaded from ImmPort. Prognostic FRGs and IRGs in the GSE14520 (n = 220) and The Cancer Genome Atlas (TCGA, n = 365) datasets were identified. Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were used for model construction. Ferroptosis expression profiles, the infiltration of immune cells, and the somatic mutation status were analyzed and compared.\nRESULTS: Twenty-seven prognostic ferroptosis- and immune-related signatures were included to construct a comprehensive index of ferroptosis and immune status (CIFI). A subgroup of patients was identified as having a high CIFI value, which was associated with a worse prognosis. This subgroup of patients had significantly up-regulated expressions of many suppressors of ferroptosis and higher fractions of immunosuppressive cells, such as cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs). Notably, somatic mutation analysis indicated that high-CIFI patients had higher levels of tumor heterogeneity and higher mutation frequencies of genes like TP53.\nCONCLUSION: In this work, a novel prognostic classifier was developed based on ferroptosis- and IRGs in HCC, and this classifier could be used for prognostic prediction and the selection of patients for immunotherapies and targeted therapies.", "claims": [{"id": "claim-method", "statement": "Then, the CIFI values and the clinicopathological features with prognostic significance (p < 0.05) were subjected to a multivariate Cox regression analysis, which revealed that CIFI remained an independent prognostic predictor after correction for other confounding factors (p < 0.001, Figures 8B, 9B).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33425905", "locator": "sections[15] \"Independent Prognostic Value of the CIFI Classifier\" paragraph 4", "quote": "Then, the CIFI values and the clinicopathological features with prognostic significance (p < 0.05) were subjected to a multivariate Cox regression analysis, which revealed that CIFI remained an independent prognostic predictor after correction for other confounding factors (p < 0.001, Figures 8B, 9B)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:33425905", "locator": "sections[18] \"Data Availability Statement\" paragraph 2", "quote": "The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": null, "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:33425905"], "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": "blocked", "blocked_on": "data:accession_absent", "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": [], "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": [], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": ["step:obtain_source_data blocked on data:accession_absent"]}, "data": {"state": "partial", "assets": [{"id": "source:pmid:33425905", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fcell.2020.596679", "sha256": "sha256:276ce6826ef8d83c084de069e32c366c52cc321f77137566821295de0c3ae114", "bytes": 41293, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fcell.2020.596679", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC7785857", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "asset:table:pmid:33425905:1", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:610245bcaf9148cee9bde4cc32c7158da5079d2b1850f5d83ee32d4d96152d84", "bytes": 2978, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[3]/table-wrap[1]#T1", "version": null, "note": "Baseline characteristics of HCC patients in the GSE14520 and TCGA cohorts.", "structure": {"pmcid": "PMC7785857", "section_index": 3, "section_title": "Study Population and Data Acquisition", "row_count": 86, "column_count": 5}, "table": {"label": "TABLE 1", "caption": "Baseline characteristics of HCC patients in the GSE14520 and TCGA cohorts.", "rows": [["Clinical characteristics", "GSE14520", "TCGA"], ["", "Total (n = 220)", "%", "Total (n = 365)", "%"], ["Age", "", "", "", ""], ["<60", "178", "80.9", "165", "45.2"], ["≥60", "42", "19.1", "200", "54.8"], ["Gender", "", "", "", ""], ["Female", "30", "13.6", "119", "32.6"], ["Male", "190", "86.4", "246", "67.4"], ["T", "", "", "", ""], ["T1", "–", "–", "180", "49.3"], ["T2", "–", "–", "91", "24.9"], ["T3", "–", "–", "78", "21.4"], ["T4", "–", "–", "13", "3.6"], ["Unknown", "–", "", "3", "0.8"], ["N", "", "", "", ""], ["N0", "–", "–", "248", "67.9"], ["N1", "–", "–", "4", "1.1"], ["Nx", "–", "–", "113", "31.0"], ["M", "", "", "", ""], ["M0", "–", "–", "263", "72.1"], ["M1", "–", "–", "3", "0.8"], ["Mx", "–", "–", "99", "27.1"], ["Stage", "", "", "", ""], ["I", "93", "42.3", "170", "46.6"], ["II", "77", "35", "84", "23.0"], ["III", "48", "21.8", "83", "22.7"], ["IV", "0", "0", "4", "1.1"], ["Unknown", "2", "0.9", "24", "6.6"], ["Adjacent hepatic tissue inflammation"], ["None", "–", "–", "117", "32.1"], ["Mild", "–", "–", "98", "26.8"], ["Severe", "–", "–", "17", "4.7"], ["Unknown", "–", "–", "133", "36.4"], ["Vascular tumor cell type", "", "", "", ""], ["None", "–", "–", "205", "56.2"], ["Micro", "–", "–", "91", "24.9"], ["Macro", "–", "–", "16", "4.4"], ["Unknown", "–", "–", "53", "14.5"], ["Ishak fibrosis score", "", "", "", ""], ["No fibrosis", "–", "–", "74", "20.3"], ["Portal fibrosis", "–", "–", "31", "8.5"], ["Fibrous septa", "–", "–", "27", "7.4"], ["Nodular formation and incomplete cirrhosis", "–", "–", "9", "2.5"], ["Established cirrhosis", "–", "–", "68", "18.6"], ["Unknown", "–", "–", "156", "42.7"], ["AFP", "", "", "", ""], ["≥300", "118", "53.6", "66", "18.1"], ["<300", "99", "45", "212", "58.1"], ["Unknown", "3", "1.4", "87", "23.8"], ["Child–Pugh", "", "", "", ""], ["A", "–", "–", "216", "59.2"], ["B", "–", "–", "21", "5.8"], ["C", "–", "–", "1", "0"], ["Unknown", "–", "–", "127", "34.8"], ["Status", "", "", "", ""], ["Alive", "136", "61.8", "234", "64.4"], ["Dead", "84", "38.2", "130", "35.6"], ["Unknown", "–", "–", "1", "0"], ["HBV status", "", "", "", ""], ["AVR-CC", "56", "25.5", "–", "–"], ["CC", "155", "70.5", "–", "–"], ["Unknown", "9", "4", "–", "–"], ["Main tumor size", "", "", "", ""], ["Small", "139", "63.2", "–", "–"], ["Large", "80", "36.4", "–", "–"], ["Unknown", "1", "0", "–", "–"], ["Multi-nodular", "", "", "", ""], ["No", "175", "79.5", "–", "–"], ["Yes", "45", "20.5", "–", "–"], ["Cirrhosis", "", "", "", ""], ["No", "18", "8.2", "–", "–"], ["Yes", "202", "91.8", "–", "–"], ["BCLC", "", "", "", ""], ["A", "148", "67.3", "–", "–"], ["B", "22", "10", "–", "–"], ["C", "28", "12.7", "–", "–"], ["Unknown", "22", "10", "–", "–"], ["Histologic grade", "", "", "", ""], ["G1", "", "", "55", "15.1"], ["G2", "", "", "175", "47.9"], ["G3", "", "", "118", "32.3"], ["G4", "", "", "12", "3.3"], ["Unknown", "", "", "5", "1.3"], ["CIFI", "", "", "", ""], ["Low", "140", "63.6", "232", "63.6"], ["High", "80", "36.4", "133", "36.4"]], "row_count": 86, "column_count": 5, "numeric_cells": 169, "header_rows": 2, "locator": "section[3]/table-wrap[1]#T1"}}, {"id": "asset:table:pmid:33425905:2", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:4b52442717f742dd27e4ac9e7360d03f72dd332d63810b0e57b35ff627199ef6", "bytes": 1513, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[15]/table-wrap[1]#T2", "version": null, "note": "Relationships between the CIFI value and clinicopathological features of HCC patients.", "structure": {"pmcid": "PMC7785857", "section_index": 15, "section_title": "Independent Prognostic Value of the CIFI Classifier", "row_count": 32, "column_count": 7}, "table": {"label": "TABLE 2", "caption": "Relationships between the CIFI value and clinicopathological features of HCC patients.", "rows": [["Clinicopathological features", "GSE14520", "TCGA"], ["", "Low CIFI", "High CIFI", "p-Value", "Low CIFI", "High CIFI", "p-Value"], ["Age", "", "", "", "", "", ""], ["<60", "107", "71", "0.03953", "103", "62", "0.7637"], ["≥60", "33", "9", "", "129", "71", ""], ["Gender", "", "", "", "", "", ""], ["Male", "119", "71", "0.565", "170", "76", "0.002301"], ["Female", "21", "9", "", "62", "57", ""], ["AFP", "", "", "", "", "", ""], ["≤300", "87", "31", "0.001172", "149", "63", "0.05223"], [">300", "51", "48", "", "36", "28", ""], ["Stage", "", "", "", "", "", ""], ["I/II", "122", "48", "2.49E-06", "178", "76", "1.86E-05"], ["III/IV", "16", "32", "", "38", "49", ""], ["Cirrhosis", "", "", "", "", "", ""], ["No", "17", "1", "0.009881", "–", "–", "–"], ["Yes", "123", "79", "", "–", "–", ""], ["BCLC", "", "", "", "", "", ""], ["0/A", "119", "49", "4.88E-05", "–", "–", "–"], ["B/C", "19", "31", "", "–", "–", ""], ["Histologic grade", "", "", "", "", "", ""], ["G1 + G2", "–", "–", "–", "162", "68", "0.0003118"], ["G3 + G4", "–", "–", "", "66", "64", ""], ["Vascular invasion", "", "", "", "", "", ""], ["No", "–", "–", "–", "144", "61", "0.02296"], ["Yes", "–", "–", "", "60", "46", ""], ["Fibrosis", "", "", "", "", "", ""], ["No", "–", "–", "–", "49", "25", "0.2979"], ["Yes", "–", "–", "", "100", "35", ""], ["Child-Pugh", "", "", "", "", "", ""], ["A", "–", "–", "–", "151", "65", "1"], ["B/C", "–", "–", "", "15", "7", ""]], "row_count": 32, "column_count": 7, "numeric_cells": 76, "header_rows": 2, "locator": "section[15]/table-wrap[1]#T2"}}], "gaps": []}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "Then, the CIFI values and the clinicopathological features with prognostic significance (p < 0.05) were subjected to a multivariate Cox regression analysis, which revealed that CIFI remained an independent prognostic predictor after correction for other confounding factors (p < 0.001, Figures 8B, 9B)."}}, {"id": "method-2", "family": "group_comparison", "specific": "wilcoxon", "label": "Group comparison", "dsl_operations": [], "missing_operations": ["group_comparison_wilcoxon"], "expressible": false, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "Wilcoxon"}}, {"id": "method-3", "family": "survival_analysis", "specific": "log_rank_test", "label": "Survival analysis", "dsl_operations": ["logrank_test"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "log-rank"}}], "targets": [], "gaps": ["method.reader_differs_from_extractor"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "blocked", "tier": "R4", "blocking_axis": "data", "blocked_on": "data:accession_absent", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["cox_ph"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: cox_proportional_hazards."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R4", "reachable": false, "accessions": ["GSE14520/GPL3921"], "resolved_accessions": [], "statements": ["The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s."], "basis": "The paper names GSE14520/GPL3921, but the accession does not resolve in the repository (no reason recorded), so the data cannot be reached from here. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["cox_ph"], "assets": ["source:pmid:33425905", "asset:table:pmid:33425905:1", "asset:table:pmid:33425905:2"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:None"]}, "gaps": ["data:accession_absent"]}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-10-31T18:26:08Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 3, "usage": {"prompt_tokens": 31844, "completion_tokens": 2456, "cached_tokens": 784}}, "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:33425905", "type": "paper", "label": "pmid:33425905"}, {"id": "source:pmid:33425905", "type": "manuscript", "label": "PMID 33425905 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:33425905", "type": "paper", "label": "pmid:33425905"}, {"id": "source:pmid:33425905", "type": "manuscript", "label": "PMID 33425905 full text"}, {"id": "data:geo:None", "type": "dataset", "label": "GEO None"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-33425905", "type": "extraction", "used": ["source:pmid:33425905"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-None", "type": "accession_resolution", "used": ["data:geo:None"], "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:33425905", "parent_hash": "sha256:f1a940128eefcae1ab28bab314da58ee2fe95cef0dfa09c968a6038e6ac978c3", "fork_of": null, "generation": 6}, "gaps": ["execution.not_run", "method.reader_differs_from_extractor", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:obtain_source_data blocked on data:accession_absent"], "assays": [{"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Then, the CIFI values and the clinicopathological features with prognostic significance (p < 0.05) were subjected to a multivariate Cox regression analysis, which revealed that CIFI remained an independent prognostic predictor after correction for other confounding factors (p < 0.001, Figures 8B, 9B)."], "order_basis": "analysis_only", "id": "assay:1"}]}