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Sphingosine\u20101\u2010phosphate (S1P) regulates cardiovascular and immune responses, predominantly through S1P receptors, but whether it also modulates macrophage\u2010associated inflammatory signaling during LPS\u2010induced cardiac injury remains incompletely understood. This study investigated the role of the RASGRP1\u2013S100A9\u2013NLRP3 signaling axis in the cardioprotective effects of S1P. Transcriptomic and single\u2010cell RNA\u2010sequencing analyses were used to identify inflammation\u2010associated candidate genes and their cellular distribution. Male Sprague\u2010Dawley rats received a single intraperitoneal injection of LPS (8\u2009mg\/kg) followed by S1P treatment for 6 weeks. Histopathology, echocardiography, serum cardiac\u2010injury markers, oxidative\u2010stress indices, inflammatory cytokines, Western blotting, and cellular metabolic\u2010flux assays were evaluated. RAW264.7 macrophages were used for mechanistic cellular studies. RASGRP1 or NLRP3 overexpression and S100A9\u2010R101Q mutation were used to assess functional contributions. Molecular docking and molecular\u2010dynamics simulations were complemented by SPR, MST, CETSA, DARTS, and Co\u2010IP assays to evaluate S1P\u2013RASGRP1 target engagement and pathway\u2010associated protein interactions. Bioinformatic analyses identified RASGRP1 as a macrophage\u2010enriched, inflammation\u2010associated hub gene. In LPS\u2010treated rats, S1P reduced myocardial inflammatory injury and collagen deposition, improved ejection fraction and fractional shortening, and decreased cardiac\u2010injury, oxidative\u2010stress, and inflammatory markers. In RAW264.7 macrophages, S1P attenuated inflammatory and oxidative\u2010stress responses, restored oxidative phosphorylation and glycolytic capacity, and reduced the abundance of RASGRP1, S100A9, NLRP3, and ASC. SPR and MST supported a concentration\u2010dependent biophysical interaction between S1P and RASGRP1; CETSA and DARTS provided complementary target\u2010stability evidence. The molecular\u2010dynamics trajectory showed substantial rearrangement of S1P from the starting pose before reaching a plateau and therefore supports conformational sampling rather than preservation of the original docked pose. Co\u2010IP supported protein associations within the proposed inflammatory network. RASGRP1 or NLRP3 overexpression attenuated several S1P\u2010associated protective effects. The S100A9\u2010R101Q mutation also weakened several S1P\u2010associated protective responses. SPR indicated a lower apparent dissociation constant for R101Q than for WT S100A9 after model\u2010specific fitting, which is consistent with stronger or more persistent NLRP3 binding rather than loss of the S100A9\u2013NLRP3 interaction. S1P mitigates LPS\u2010induced inflammatory cardiac injury in association with altered macrophage RASGRP1\u2013S100A9\u2013NLRP3 signaling. Biophysical and target\u2010stability assays support direct engagement of RASGRP1 by S1P. However, these findings do not establish RASGRP1 as the sole mediator of S1P activity, exclude contributions from canonical S1P receptor signaling, or demonstrate a strictly linear RASGRP1\u2013S100A9\u2013NLRP3 signaling cascade. Because the LPS model primarily represents endotoxemia\u2010associated inflammatory cardiac injury, extrapolation of these findings to classical viral or autoimmune myocarditis should be made with caution.<\/jats:p>","DOI":"10.1002\/ddr.70391","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:16:04Z","timestamp":1790075764000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sphingosine\u20101\u2010Phosphate Attenuates LPS\u2010Induced Inflammatory Cardiac Injury in Association With RASGRP1\u2013S100A9\u2013NLRP3 Signaling"],"prefix":"10.1002","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7610-9526","authenticated-orcid":false,"given":"Chaofu","family":"Yue","sequence":"first","affiliation":[{"name":"Department of Intensive Care Unit Affiliated Qujing Hospital of Kunming Medical University, Qujing Central Hospital of Yunnan Province Qujing Yun Nan 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