{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:44:38Z","timestamp":1793727878728,"version":"4.6.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Sepsis is a life-threatening organ dysfunction syndrome with persistently high global mortality, driven by dysregulated host immune response. Existing single-target therapies fail to simultaneously address hyperinflammation and impaired tissue repair, leading to limited clinical efficacy and repeated translational failures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Integrated multi-omics datasets (scRNA-seq, miRNA-seq, blood\/lung RNA-seq) delineated immune cell dynamics and dysregulated pathways in sepsis. Guided by omics findings, we designed two small-molecule combinations (C1, C2) targeting the identified pathways. Their efficacy and mechanism were validated in\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      sepsis models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Septic patients showed a hallmark immune remodeling signature: expansion of pro-inflammatory myeloid cells (neutrophils, monocytes) and depletion of protective lymphoid cells (B cells, NK cells). A dual-pathway small-molecule combination C2 targeting inflammatory cascades and Hippo\/Wnt regenerative pathways, exerted significant synergistic therapeutic effects. It robustly rebalanced systemic and organ-specific inflammation (suppressed\n                      <jats:italic>Il1b<\/jats:italic>\n                      ,\n                      <jats:italic>Il6<\/jats:italic>\n                      ,\n                      <jats:italic>Nos2<\/jats:italic>\n                      ,\n                      <jats:italic>Tnfa<\/jats:italic>\n                      ; elevated\n                      <jats:italic>Il10<\/jats:italic>\n                      ,\n                      <jats:italic>Arg1<\/jats:italic>\n                      ,\n                      <jats:italic>Tgfb<\/jats:italic>\n                      ,\n                      <jats:italic>Nos3<\/jats:italic>\n                      )\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      , ameliorated multi-organ injury, and improved 7-day survival in septic mice from 20% (untreated) to 70%. Single-compound control experiments confirmed that the enhanced efficacy of C2 stems from dual-pathway synergy, not individual components.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study revealed immune dysregulation as the core pathogenesis of sepsis. The C2 combination simultaneously mitigates hyperinflammation and promotes tissue repair, providing a novel, mechanism-driven, and clinically translatable combination strategy for sepsis management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1809540","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:27:05Z","timestamp":1778819225000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrated multi-omics deciphers sepsis immune dysregulation: a dual-pathway targeted small-molecule therapy improves survival and ameliorates multi-organ dysfunction"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiawen","family":"Duan","sequence":"first","affiliation":[{"name":"Guangxi Health Commission Key Laboratory of Diagnosis and Treatment of Acute Respiratory Distress Syndrome, Guangxi Academy of Medical Sciences","place":["Nanning, Guangxi, China"]},{"name":"Institute of Infectious Diseases and Emergency and Critical Care Medicine, Guangxi Academy of Medical Sciences","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The People\u2019s Hospital of Guangxi Zhuang Autonomous Region","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunlin","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The People\u2019s Hospital of Guangxi Zhuang Autonomous Region","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huirong","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Unit, The People\u2019s Hospital of Guangxi Zhuang Autonomous Region","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Chi","sequence":"additional","affiliation":[{"name":"Guangxi Health Commission Key Laboratory of Diagnosis and Treatment of Acute Respiratory Distress Syndrome, Guangxi Academy of Medical Sciences","place":["Nanning, Guangxi, China"]},{"name":"Institute of Infectious Diseases and Emergency and Critical Care Medicine, Guangxi Academy of Medical Sciences","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiting","family":"Feng","sequence":"additional","affiliation":[{"name":"Graduate School, Youjiang Medical University for Nationalities","place":["Baise, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangxi Zhuang Autonomous Region Engineering Research Center for 3D Printing in Smart Biomanufacturing and Application, Guangxi Academy of Medical Sciences","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulin","family":"Xiang","sequence":"additional","affiliation":[{"name":"Guangxi Health Commission Key Laboratory of Diagnosis and Treatment of Acute Respiratory Distress Syndrome, Guangxi Academy of Medical Sciences","place":["Nanning, Guangxi, China"]},{"name":"Department of Intensive Care Unit, The People\u2019s Hospital of Guangxi Zhuang Autonomous Region","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xiong","sequence":"additional","affiliation":[{"name":"Guangxi Health Commission Key Laboratory of Diagnosis and Treatment of Acute Respiratory Distress Syndrome, Guangxi Academy of Medical Sciences","place":["Nanning, Guangxi, China"]},{"name":"Department of Intensive Care Unit, The People\u2019s Hospital of Guangxi Zhuang Autonomous Region","place":["Nanning, Guangxi, China"]},{"name":"Guangxi Clinical Research Center for Critical Treatment of Major Infectious Diseases","place":["Nanning, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-024-07694-z","article-title":"Sepsis: Key insights, future directions, and immediate goals. 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