{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:09:02Z","timestamp":1793138942057,"version":"4.5.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"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>Background<\/jats:title>\n                    <jats:p>Sepsis-associated liver injury (SALI) increases mortality in critically ill patients but lacks targeted treatments. Although the natural compound Paeoniflorin shows anti-inflammatory and immunomodulatory potential, its specific function and mechanism in SALI remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A murine model of polymicrobial sepsis was established using cecal ligation and puncture (CLP). Male C57BL\/6 mice were randomly allocated to Sham, CLP, CLP+Paeoniflorin (30, 60, 120 mg\/kg), CLP+Paeoniflorin+TLR4 agonist (RS09 TFA), and Paeoniflorin-only control groups. Liver injury was assessed through serum ALT\/AST measurements, histopathological evaluation, and TUNEL apoptosis assay. Hepatic inflammatory cytokine expression was quantified by qPCR. Macrophage polarization was analyzed via immunohistochemistry for F4\/80, CD86 (M1), and CD206 (M2) markers. TLR4\/NF-\u03baB pathway activity was examined using Western blotting and immunohistochemistry. Transcriptomic profiling was performed through RNA sequencing and KEGG pathway analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Paeoniflorin administration significantly attenuated CLP-induced elevations in serum ALT and AST levels in a dose-dependent manner, ameliorated histopathological liver damage, and reduced hepatocyte apoptosis. Treatment with Paeoniflorin substantially downregulated hepatic mRNA expression of pro-inflammatory cytokines (IL-6, TNF-\u03b1, IL-1\u03b2). Immunohistochemical analysis revealed that Paeoniflorin treatment was associated with a shift in macrophage marker expression, characterized by a reduction in cells co-staining for F4\/80 and the classic M1 marker CD86, and an increase in cells co-staining for F4\/80 and the classic M2 marker CD206. This suggests a potential modulation of macrophage polarization balance towards an anti-inflammatory phenotype. Both transcriptomic and protein analyses confirmed that Paeoniflorin suppressed activation of the TLR4\/NF-\u03baB signaling pathway. The protective effects of Paeoniflorin were completely abolished by co-administration of the TLR4 agonist RS09 TFA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Paeoniflorin confers protection against sepsis-induced liver injury by modulating macrophage polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype through inhibition of the TLR4\/NF-\u03baB signaling pathway. These findings identify Paeoniflorin as a promising candidate for further development as an immunomodulatory therapy for SALI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1751550","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T05:28:17Z","timestamp":1768886897000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Paeoniflorin attenuates sepsis-induced liver injury by reprogramming macrophage polarization via the TLR4\/NF-\u03baB pathway"],"prefix":"10.3389","volume":"16","author":[{"given":"Zhiwei","family":"Rong","sequence":"first","affiliation":[{"name":"Postgraduate Training Base of Jinzhou Medical University, Shanghai East Hospital","place":["Shanghai, China"]},{"name":"Department of Pain Management, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baitian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, The Second Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunzheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pain Management, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijun","family":"Liao","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base of Jinzhou Medical University, Shanghai East Hospital","place":["Shanghai, China"]},{"name":"Department of Pain Management, Shanghai East Hospital, Tongji University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S222296","article-title":"Paclitaxel alleviated sepsis-induced acute lung injury by activating MUC1 and suppressing TLR-4\/NF-kappaB pathway","volume":"13","author":"Wang","year":"2019","journal-title":"Drug Des Devel Ther"},{"key":"B2","doi-asserted-by":"crossref","first-page":"e18761429387280","DOI":"10.2174\/0118761429387280250506114040","article-title":"Stimulation of soluble guanylyl cyclase (sGC) by cinaciguat attenuates sepsisinduced cardiac injury","volume":"17","author":"Li","year":"2024","journal-title":"Curr Mol Pharmacol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"368504251352747","DOI":"10.1177\/00368504251352747","article-title":"The application of therapeutic plasma exchange in sepsis and septic shock: A narrative review","volume":"108","author":"Wu","year":"2025","journal-title":"Sci Prog"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S523991","article-title":"Xuebijing injection alleviates sepsis-induced acute lung injury by inhibition of cell apoptosis and inflammation through the hippo pathway","volume":"18","author":"Ling","year":"2025","journal-title":"J Inflammation Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines13010180","article-title":"To hemoadsorb or not to hemoadsorb-do we have the answer yet? 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