{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T07:24:49Z","timestamp":1768980289412,"version":"3.49.0"},"reference-count":47,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Staphylococcus aureus<\/jats:italic>\n                      (\n                      <jats:italic>S. aureus<\/jats:italic>\n                      ) pneumonia constitutes a lethal respiratory infection with persistently high clinical mortality. Although programmed cell death (PCD) pathways are implicated in diverse disease processes, their mechanistic roles in\n                      <jats:italic>S. aureus<\/jats:italic>\n                      pneumonia pathogenesis, particularly as dual-purpose biomarkers for early diagnosis and therapeutic targeting remain insufficiently characterized.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      High-throughput RNA sequencing was conducted on\n                      <jats:italic>S. aureus<\/jats:italic>\n                      challenged murine pulmonary tissues to delineate pneumonia-associated differentially expressed genes (DEGs). Through bioinformatics screening, we established a PCD -related gene signature and validated its clinical relevance via transcriptomic profiling of peripheral blood samples from confirmed\n                      <jats:italic>S. aureus<\/jats:italic>\n                      pneumonia patients. Machine learning (including LASSO regression and SVM-RFE algorithms) were employed to prioritize characteristic biomarkers, followed by construction of a risk-prediction nomogram with Receiver Operating Characteristic (ROC) curve validation. Multidimensional analyses encompassing immune cell infiltration patterns and DSigDB based drug discovery were performed, supplemented by molecular docking simulations and qPCR confirmation of core regulatory elements.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Whole-transcriptome analysis revealed 71 PCD-related DEGs (DE-PCDs) with conserved cross-species dysregulation (19 genes in human specimens). Machine learning identified 11 hub genes modulating apoptosis, necroptosis, autophagy, and ferroptosis interconnections. A four-gene diagnostic panel (NAMPT, NFKBIA, SLC40A1, PRKCQ) demonstrated high predictive accuracy (AUC\u2009=\u20090.92) via nomogram modeling. Significant correlations emerged between biomarkers and neutrophil\/T-cell infiltration dynamics, while computational drug screening identified 27 candidate compounds targeting these determinants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This investigation delineates PCD-mediated regulatory networks in\n                      <jats:italic>S. aureus<\/jats:italic>\n                      pneumonia, establishing a clinically translatable biomarker panel with theranostic potential against infectious pulmonary inflammation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0339560","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T18:38:26Z","timestamp":1768934306000},"page":"e0339560","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell death-related gene signatures as dual-function biomarkers: Early diagnosis and therapeutic targeting in Staphylococcus aureus pneumonia"],"prefix":"10.1371","volume":"21","author":[{"given":"Cao","family":"Qing","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanjuan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaomian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yien","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiong","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianxia","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9273-0809","authenticated-orcid":true,"given":"Lu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"issue":"6","key":"pone.0339560.ref001","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s41579-023-00852-y","article-title":"Staphylococcus aureus host interactions and adaptation","volume":"21","author":"BP Howden","year":"2023","journal-title":"Nat Rev Microbiol"},{"issue":"3","key":"pone.0339560.ref002","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1128\/CMR.10.3.505","article-title":"Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks","volume":"10","author":"J Kluytmans","year":"1997","journal-title":"Clin Microbiol Rev"},{"issue":"3","key":"pone.0339560.ref003","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/20477724.2023.2285187","article-title":"Staphylococcus aureus epidemiology, pathophysiology, clinical manifestations and application of nano-therapeutics as a promising approach to combat methicillin resistant Staphylococcus aureus","volume":"118","author":"RHF Bashabsheh","year":"2024","journal-title":"Pathog Glob Health"},{"issue":"4","key":"pone.0339560.ref004","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.3390\/jcm12041298","article-title":"Ventilator-associated pneumonia in COVID-19 patients admitted in intensive care units: relapse, therapeutic failure and attributable mortality-a multicentric observational study from the outcomerea network","volume":"12","author":"P-H Wicky","year":"2023","journal-title":"J Clin Med"},{"key":"pone.0339560.ref005","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3389\/fcimb.2020.00107","article-title":"Prevalence and Therapies of Antibiotic-Resistance in Staphylococcus aureus","volume":"10","author":"Y Guo","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"issue":"4","key":"pone.0339560.ref006","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41579-018-0147-4","article-title":"Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research","volume":"17","author":"NA Turner","year":"2019","journal-title":"Nat Rev Microbiol"},{"issue":"3","key":"pone.0339560.ref007","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s10096-015-2566-8","article-title":"Staphylococcus aureus bacteremic pneumonia","volume":"35","author":"C De la Calle","year":"2016","journal-title":"Eur J Clin Microbiol Infect Dis"},{"issue":"1","key":"pone.0339560.ref008","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2014.570","article-title":"Die for the community: an overview of programmed cell death in bacteria","volume":"6","author":"N Allocati","year":"2015","journal-title":"Cell Death Dis"},{"issue":"10","key":"pone.0339560.ref009","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2419620122","article-title":"Coronavirus endoribonuclease antagonizes ZBP1-mediated necroptosis and delays multiple cell death pathways","volume":"122","author":"M Evdokimova","year":"2025","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0339560.ref010","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3390\/pathogens14010043","article-title":"PANoptosis in bacterial infections: a double-edged sword balancing host immunity and pathogenesis","volume":"14","author":"X He","year":"2025","journal-title":"Pathogens"},{"issue":"5","key":"pone.0339560.ref011","doi-asserted-by":"crossref","DOI":"10.1152\/ajpcell.00246.2022","article-title":"Different modalities of host cell death and their impact on Mycobacterium tuberculosis infection","volume":"323","author":"A Nisa","year":"2022","journal-title":"Am J Physiol Cell Physiol"},{"issue":"2","key":"pone.0339560.ref012","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1093\/infdis\/jiae252","article-title":"Neutrophil extracellular traps: an emerging therapeutic target to improve infectious disease outcomes","volume":"230","author":"A Meier","year":"2024","journal-title":"J Infect Dis"},{"issue":"15","key":"pone.0339560.ref013","first-page":"11755","article-title":"Types of cell death and their relations to host immunological pathways","volume":"16","author":"K-C Lu","year":"2024","journal-title":"Aging (Albany NY)"},{"issue":"5","key":"pone.0339560.ref014","article-title":"Intracellular Staphylococcus aureus and host cell death pathways","volume":"23","author":"YM Soe","year":"2021","journal-title":"Cell Microbiol"},{"key":"pone.0339560.ref015","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkv1070","article-title":"KEGG as a reference resource for gene and protein annotation","volume":"44","author":"M Kanehisa","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pone.0339560.ref016","doi-asserted-by":"crossref","first-page":"107780","DOI":"10.1016\/j.compbiomed.2023.107780","article-title":"Identification and analysis of diverse cell death patterns in diabetic kidney disease using microarray-based transcriptome profiling and single-nucleus RNA sequencing","volume":"169","author":"Y Luo","year":"2024","journal-title":"Comput Biol Med"},{"issue":"1","key":"pone.0339560.ref017","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"M Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"pone.0339560.ref018","article-title":"The GeneCards suite: from gene data mining to disease genome sequence analyses","volume":"54","author":"G Stelzer","year":"2016","journal-title":"Curr Protoc Bioinformatics"},{"issue":"6","key":"pone.0339560.ref019","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"A Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"pone.0339560.ref020","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"M Gillespie","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"9","key":"pone.0339560.ref021","first-page":"5560","article-title":"Sparse SVM for Sufficient Data Reduction","volume":"44","author":"S Zhou","year":"2022","journal-title":"IEEE Trans Pattern Anal Mach Intell"},{"key":"pone.0339560.ref022","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1007\/s10295-019-02197-z","article-title":"Genome mining for lasso peptides: past, present, and future","volume":"46","author":"WL Cheung-Lee","year":"2019","journal-title":"J Ind Microbiol Biotechnol"},{"issue":"3","key":"pone.0339560.ref023","doi-asserted-by":"crossref","DOI":"10.1111\/cpr.13376","article-title":"Comprehensive analysis of pyroptosis-related gene signatures for glioblastoma immune microenvironment and target therapy","volume":"56","author":"Z Wang","year":"2023","journal-title":"Cell Prolif"},{"issue":"15","key":"pone.0339560.ref024","doi-asserted-by":"crossref","first-page":"2595","DOI":"10.1093\/bioinformatics\/btv153","article-title":"PRROC: computing and visualizing precision-recall and receiver operating characteristic curves in R","volume":"31","author":"J Grau","year":"2015","journal-title":"Bioinformatics"},{"issue":"1","key":"pone.0339560.ref025","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s13148-019-0730-1","article-title":"Statistical predictions with glmnet","volume":"11","author":"S Engebretsen","year":"2019","journal-title":"Clin Epigenetics"},{"key":"pone.0339560.ref026","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.2147\/IDR.S500523","article-title":"Prognostic Factors and Nomogram for Klebsiella pneumoniae Infections in Intensive Care Unit","volume":"18","author":"C Du","year":"2025","journal-title":"Infect Drug Resist"},{"issue":"5","key":"pone.0339560.ref027","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"AM Newman","year":"2015","journal-title":"Nat Methods"},{"key":"pone.0339560.ref028","doi-asserted-by":"crossref","first-page":"6072438","DOI":"10.1155\/2023\/6072438","article-title":"Bioinformatics Analysis of the Inflammation-Associated lncRNA-mRNA coexpression network in type 2 diabetes","volume":"2023","author":"L Huang","year":"2023","journal-title":"J Renin Angiotensin Aldosterone Syst"},{"key":"pone.0339560.ref029","doi-asserted-by":"crossref","first-page":"1584350","DOI":"10.3389\/fimmu.2025.1584350","article-title":"Decoding multiple myeloma: single-cell insights into tumor heterogeneity, immune dynamics, and disease progression","volume":"16","author":"Z Zhao","year":"2025","journal-title":"Front Immunol"},{"key":"pone.0339560.ref030","doi-asserted-by":"crossref","first-page":"9002021","DOI":"10.1155\/2023\/9002021","article-title":"Genetic variants associated with high susceptibility of premature ischemic stroke","volume":"2023","author":"I Isordia-Salas","year":"2023","journal-title":"J Renin Angiotensin Aldosterone Syst"},{"key":"pone.0339560.ref031","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkad1040","article-title":"DGIdb 5.0: rebuilding the drug-gene interaction database for precision medicine and drug discovery platforms","volume":"52","author":"M Cannon","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"17","key":"pone.0339560.ref032","doi-asserted-by":"crossref","first-page":"4772","DOI":"10.1038\/s44318-025-00515-z","article-title":"Macrophages form dendrite-like pseudopods to enhance bacterial ingestion","volume":"44","author":"C Fan","year":"2025","journal-title":"EMBO J"},{"issue":"6","key":"pone.0339560.ref033","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/s41419-020-2517-x","article-title":"mTOR-Myc axis drives acinar-to-dendritic cell transition and the CD4+ T cell immune response in acute pancreatitis","volume":"11","author":"D Xu","year":"2020","journal-title":"Cell Death Dis"},{"issue":"6","key":"pone.0339560.ref034","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.ijmm.2017.09.013","article-title":"Staphylococcus aureus strategies to evade the host acquired immune response","volume":"308","author":"O Goldmann","year":"2018","journal-title":"Int J Med Microbiol"},{"issue":"6616","key":"pone.0339560.ref035","doi-asserted-by":"crossref","DOI":"10.1126\/science.abq0132","article-title":"A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin","volume":"378","author":"Q Chai","year":"2022","journal-title":"Science"},{"issue":"40","key":"pone.0339560.ref036","article-title":"Human cytomegalovirus UL36 inhibits IRF3-dependent immune signaling to counterbalance its immunoenhancement as apoptotic inhibitor","volume":"9","author":"Y Ren","year":"2023","journal-title":"Sci Adv"},{"key":"pone.0339560.ref037","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.2147\/JIR.S452608","article-title":"Identification and Analysis of PANoptosis-related genes in sepsis-induced lung injury by bioinformatics and experimental verification","volume":"17","author":"Z Yang","year":"2024","journal-title":"J Inflamm Res"},{"issue":"12","key":"pone.0339560.ref038","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1011892","article-title":"Pathogen-driven nucleotide overload triggers mitochondria-centered cell death in phagocytes","volume":"19","author":"N Schwermann","year":"2023","journal-title":"PLoS Pathog"},{"issue":"1","key":"pone.0339560.ref039","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s12967-025-06161-7","article-title":"Staphylococcus aureus induces mitophagy via the HDAC11\/IL10 pathway to sustain intracellular survival","volume":"23","author":"Y Yang","year":"2025","journal-title":"J Transl Med"},{"issue":"17","key":"pone.0339560.ref040","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.3390\/ani12172218","article-title":"Staphylococcus aureus-induced necroptosis promotes mitochondrial damage in goat endometrial epithelial cells","volume":"12","author":"Y Yi","year":"2022","journal-title":"Animals (Basel)"},{"key":"pone.0339560.ref041","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jare.2023.09.042","article-title":"IFP35 aggravates Staphylococcus aureus infection by promoting Nrf2-regulated ferroptosis","volume":"62","author":"M Dai","year":"2024","journal-title":"J Adv Res"},{"key":"pone.0339560.ref042","doi-asserted-by":"crossref","first-page":"102237","DOI":"10.1016\/j.redox.2022.102237","article-title":"NAMPT mitigates colitis severity by supporting redox-sensitive activation of phagocytosis in inflammatory macrophages","volume":"50","author":"SM Hong","year":"2022","journal-title":"Redox Biol"},{"key":"pone.0339560.ref043","first-page":"2843990","article-title":"MicroRNA-147a Targets SLC40A1 to Induce Ferroptosis in Human Glioblastoma","volume":"2022","author":"P Xu","year":"2022","journal-title":"Anal Cell Pathol (Amst)"},{"issue":"7","key":"pone.0339560.ref044","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/s41419-024-06902-4","article-title":"Erianin induces ferroptosis in GSCs via REST\/LRSAM1 mediated SLC40A1 ubiquitination to overcome TMZ resistance","volume":"15","author":"M Mansuer","year":"2024","journal-title":"Cell Death Dis"},{"issue":"1","key":"pone.0339560.ref045","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1080\/15548627.2022.2059170","article-title":"Identification of HPCAL1 as a specific autophagy receptor involved in ferroptosis","volume":"19","author":"X Chen","year":"2023","journal-title":"Autophagy"},{"issue":"1","key":"pone.0339560.ref046","doi-asserted-by":"crossref","first-page":"15351","DOI":"10.1038\/s41598-024-66003-2","article-title":"NF-\u03baB inhibitor alpha controls SARS-CoV-2 infection in ACE2-overexpressing human airway organoids","volume":"14","author":"CR Simoneau","year":"2024","journal-title":"Sci Rep"},{"issue":"12","key":"pone.0339560.ref047","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1080\/15548627.2024.2372215","article-title":"Extracellular NCOA4 is a mediator of septic death by activating the AGER-NFKB pathway","volume":"20","author":"J Liu","year":"2024","journal-title":"Autophagy"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0339560","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T18:38:33Z","timestamp":1768934313000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0339560"}},"subtitle":[],"editor":[{"given":"Nan","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":47,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1,20]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0339560","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}