{"doi":"10.1016/j.ebiom.2020.102952","title":"Sphingosine 1-phosphate escapes the Catch-22 of sepsis prevention and mitigation therapies","abstract":"Sepsis is defined as life-threatening organ dysfunction as a consequence of a dysregulated host immune response to infection and is the leading cause of mortality across the globe [1Singer M Deutschman CS Seymour CW et al.The third international consensus definitions for sepsis and septic shock (Sepsis-3).JAMA. 2016; 315: 801Crossref PubMed Scopus (13741) Google Scholar]. Septic organ dysfunction leads to a 2-2•5 times greater risk of death, and patients that progress to septic shock have hospital mortality rates greater than 40%. With few options available for prevention or treatment, antibiotics and supportive therapies are initiated empirically. The excessive amplification of proinflammatory cytokines, and other inflammatory mediators, that are essential for the deterioration of organ function is called a cytokine storm, a relatively obscure term until recently. The conspicuous inflammation of a sepsis cytokine storm has been unsuccessfully targeted in clinical trials, particularly by antibodies that inhibit cytokine signaling [2Nedeva C Menassa J Puthalakath H Sepsis: inflammation is a necessary evil.Front Cell Dev Biol. 2019; 7: 108Crossref PubMed Scopus (140) Google Scholar]. In some cases, cytokine suppressive therapies increased sepsis mortality. A similar barrier exists to utilizing another drug in sepsis, the anthracycline epirubicin [3Figueiredo N Chora A Raquel H et al.Anthracyclines induce DNA damage response-mediated protection against severe sepsis.Immunity. 2013; 39: 874-884Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar]. Mechanistically, epirubicin could prevent or mitigate early sepsis hormetically by activating DNA damage responses and autophagy pathways, reducing pro-inflammatory cytokines and markers of tissue damage. While 0•6 µg/kg epirubicin administration in combination with a broad-spectrum antibiotic could extend the therapeutic window up to 24 h beyond sepsis induction, higher doses dramatically increased sepsis lethality. In this issue of EBioMedicine, Weigel and colleagues demonstrate that the beneficial aspects of epirubicin treatment in experimental sepsis can be ascribed to modulation of sphingosine 1-phosphate (S1P) metabolic and signaling pathways and propose that their direct modulation may be more efficacious and less fraught [4Weigel C Hüttner SS Ludwig K et al.S1P lyase inhibition protects against sepsis by promoting disease tolerance via the S1P/S1PR3 axis.EBioMedicine. 2020; 58102898Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. They report that 0•6 µg/kg epirubicin significantly suppressed upregulation of the S1P degradative enzyme S1P lyase (SPL) in lung tissue and peripheral blood cells of mice with experimental sepsis, increasing local S1P concentrations. SPL expression and activity are responsive to cell stress, and its catabolism of S1P decreases local S1P concentrations and regulates autophagy in a cell type-specific manner [5Saba JD Fifty years of lyase and a moment of truth: sphingosine phosphate lyase from discovery to disease.J Lipid Res. 2019; 60: 456-463Summary Full Text Full Text PDF PubMed Scopus (50) Google Scholar]. S1P is a critical bioactive lipid regulator of the vascular and immune systems, which are both integral to sepsis development. Specific S1P signals are transduced by cognate G protein-coupled receptors, S1P1-5, responding to S1P concentrations tightly controlled by specific synthetic and catabolic enzymes [6Blaho VA Druggable sphingolipid pathways: experimental models and clinical opportunities.in: Kihara Y Druggable lipid signaling pathways. Springer Nature Switzerland AG, Basel2020https://doi.org/10.1007/978-3-030-50621-6_6Crossref Scopus (3) Google Scholar]. Plasma S1P concentrations of sepsis patients inversely correlate with both disease severity and mortality, a relationship also seen in experimental sepsis [4Weigel C Hüttner SS Ludwig K et al.S1P lyase inhibition protects against sepsis by promoting disease tol","journal":"EBioMedicine","year":2020,"id":116871,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":545780,"name":"Victoria A. Blaho","orcid":"0000-0001-8499-2278","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-18T23:13:47.803267Z","pmid":"32805627","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}