{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T05:07:05Z","timestamp":1779944825867,"version":"3.53.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis is a life-threatening, heterogeneous syndrome with high mortality. This heterogeneity undermines current \u201cone-size-fits-all\u201d therapies and conventional biomarkers (e.g., PCT) lack prognostic power. A critical need exists to identify patient-specific endotypes and causal-driven therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed a synergistic multi-omics strategy to identify causal drivers of sepsis. First, we used single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (GSE175453) to identify the most pathologically relevant immune cell subpopulation. Next, we used marker genes from this subset as exposures in a two-sample Mendelian randomization (MR) study, using summary statistics from a large-scale sepsis GWAS (11,643 cases\/474,841 controls; ieu-b-4980) and eQTL data (eQTLGen) to validate causal relationships. Findings were explored via in-silico functional-genomics (GSEA, GSVA) and validated via qPCR in a clinical cohort (5 sepsis vs. 5 healthy controls).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      scRNA-seq analysis identified activated CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells (Act.CD4T) as the cell subset contributing most significantly to sepsis pathogenesis. From 81 Act.CD4T marker genes, MR analysis identified four genes with a significant causal effect on sepsis risk: RPLP0 was identified as a causal risk factor (OR: 1.272; 95% CI: 1.031\u20131.569), while CD52 (OR: 0.903), RPS15A (OR: 0.954), and RPS18 (OR: 0.908) were identified as causal protective factors (all $p&amp;lt;0.05$). Clinical qPCR validation confirmed that RPLP0 was significantly upregulated in sepsis patients, while CD52, RPS15A, and RPS18 were downregulated. Functional analysis revealed these genes converge on a novel \u201cMetabolism\u2013Proteostasis\u2013Immunity\u201d regulatory axis, where RPLP0 drives a pathogenic program (HIF-1, IL-17, ERS) and RPS15A\/RPS18 mediate a protective program (AMPK, mTORC1 inhibition).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study is to integrate scRNA-seq and MR to discover cell-specific causal genes for sepsis. The identified four-gene signature provides potentially robust, causally-validated biomarkers for patient stratification and reveals the \u201cMetabolism\u2013Proteostasis\u2013Immunity\u201d axis as a critical, therapeutically-targetable node in sepsis pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1749207","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:50:35Z","timestamp":1779943835000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A synergistic multi-omics approach: causal sepsis drivers identified in activated CD4+ T cells by single-cell RNA sequencing and Mendelian randomization"],"prefix":"10.3389","volume":"16","author":[{"given":"Jun","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Emergency, Suzhou Ninth People\u2019s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Emergency, Suzhou Ninth People\u2019s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Emergency, Suzhou Ninth People\u2019s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengzhi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Emergency, Suzhou Ninth People\u2019s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Emergency, Suzhou Ninth People\u2019s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Emergency, Suzhou Ninth People\u2019s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Emergency, Suzhou Ninth People\u2019s Hospital, Suzhou Ninth Hospital Affiliated to Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"R613","DOI":"10.1152\/ajpregu.00003.2023","article-title":"Sepsis: network pathophysiology and implications for early diagnosis","volume":"324","author":"Arora","year":"2023","journal-title":"Am. 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