Paeoniflorin Alleviates LPS-Induced Inflammation and Acute Myocardial Injury by Inhibiting PI3K/Akt/ERK-Mediated HIF-1α and TLR4/MyD88/NF-κB Inflammatory Signaling.

Sepsis-induced myocardial injury (SIMI) greatly increases the mortality rate of sepsis. 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- and SIMI-related 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-κB signaling pathway, HIF-1 signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway. Molecular docking further verified the strong binding abilities of PF to PI3K, Akt1, ERK1, ERK2, HIF-1α, TLR4, and NF-κB. In LPS-induced sepsis rat model, PF pretreatment inhibited PI3K/Akt/ERK-mediated HIF-1α and TLR4/MyD88/NF-κB signaling, thereby reducing inflammation by decreasing the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) 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-MB, cTnT/TNNT2, TNNI3/cTn-I, and aspartate aminotransferase (AST). Collectively, the PI3K/Akt/ERK-mediated HIF-1α and TLR4/MyD88/NF-κB inflammation signaling appear to be the primary mechanisms through which PF exerts its beneficial effects on SIMI.