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Although paeoniflorin (PF) has been proven to improve survival in sepsis, the detailed mechanism of PF on SIMI remains elusive. In this study, network pharmacology revealed 90 overlapping targets between PF\u2010 and SIMI\u2010related targets. Analysis using the molecular complex detection (MCODE) method identified a significant module with scores exceeding 30, comprising the top 10 targets: Akt1, STAT3, CASP3, BCL2, TP53, PTGS2, CXCL8, TLR4, CCL2, and ICAM1. These targets are involved in tissue repair during inflammatory response, apoptosis, immunity, and lipopolysaccharide (LPS) immune receptor activity. The enriched pathways in inflammatory signaling, include NF\u2010\u03baB signaling pathway, HIF\u20101 signaling pathway, MAPK signaling pathway, and PI3K\u2010Akt signaling pathway. Molecular docking further verified the strong binding abilities of PF to PI3K, Akt1, ERK1, ERK2, HIF\u20101\u03b1, TLR4, and NF\u2010\u03baB. In LPS\u2010induced sepsis rat model, PF pretreatment inhibited PI3K\/Akt\/ERK\u2010mediated HIF\u20101\u03b1 and TLR4\/MyD88\/NF\u2010\u03baB signaling, thereby reducing inflammation by decreasing the levels of tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) and interleukin\u20101\u03b2 (IL\u20101\u03b2) in serum and cardiac tissue. Ultimately, PF ameliorated SIMI by improving cardiac pathological and functional changes and mitigating myocardial injury markers, such as lactate dehydrogenase (LDH), CK\u2010MB, cTnT\/TNNT2, TNNI3\/cTn\u2010I, and aspartate aminotransferase (AST). Collectively, the PI3K\/Akt\/ERK\u2010mediated HIF\u20101\u03b1 and TLR4\/MyD88\/NF\u2010\u03baB inflammation signaling appear to be the primary mechanisms through which PF exerts its beneficial effects on SIMI.<\/jats:p>","DOI":"10.1155\/mi\/2346163","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T13:50:44Z","timestamp":1763560244000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Paeoniflorin Alleviates LPS\u2010Induced Inflammation and Acute Myocardial Injury by Inhibiting PI3K\/Akt\/ERK\u2010Mediated HIF\u20101\u03b1 and TLR4\/MyD88\/NF\u2010\u03baB Inflammatory 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