{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:55:18Z","timestamp":1789073718718,"version":"build-2803163510"},"reference-count":101,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T00:00:00Z","timestamp":1753660800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX006408"],"award-info":[{"award-number":["I01BX006408"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>According to the Surviving Sepsis Campaign, 50.3% of septic shock patients received steroid\/glucocorticoid (GC) therapy. However, whether GC therapy is beneficial and who might benefit from it are hotly debated. Initial guidelines recommended GC therapy for septic patients with adrenal insufficiency, but this has since been retracted. Recent studies using animal models of adrenal insufficiency have shed light on the mechanisms, demonstrating that the adrenal stress response is a part of the host response that is essential for control inflammatory response in sepsis and the adrenal insufficiency is a risk factor for sepsis. This perspective review explores the limitations of GC therapy through the lens of GC biology, with a particular focus on the role of scavenger receptor class B type I (SR-BI) in mediating the adrenal stress response. We highlight the mechanisms of how SR-BI-mediated adrenal stress response contributes to the regulation of hyperinflammation and innate immune responses. By integrating mechanistic insights with the limitations of GC therapy, we advocate for a precision medicine approach to GC therapy in sepsis\u2013 selectively applying GC therapy for patients with adrenal insufficiency, not without.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1643395","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T05:30:42Z","timestamp":1753680642000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The Role of SR-BI in sepsis: leveraging mechanistic insights to advance precision steroid therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Ling","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-An","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature01326","article-title":"The immunopathogenesis of sepsis","volume":"420","author":"Cohen","year":"2002","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.10.012","article-title":"The immunology of sepsis","volume":"54","author":"van der Poll","year":"2021","journal-title":"Immunity"},{"key":"B5","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.molmed.2014.01.007","article-title":"Why have clinical trials in sepsis failed","volume":"20","author":"Marshall","year":"2014","journal-title":"Trends Mol Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.792448","article-title":"Overlapping but disparate inflammatory and immunosuppressive responses to SARS-coV-2 and bacterial sepsis: an immunological time course analysis","volume":"12","author":"Loftus","year":"2021","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1097\/01.ccm.0000510159.48167.31","article-title":"GLUCOCORTICOID ONLY BENEFITS SEPTIC MICE WITH ADRENAL INSUFFICIENCY: A PRECISION MEDICINE APPROACH","volume":"44","author":"Li","year":"2016","journal-title":"Crit Care Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1110516","article-title":"Relative adrenal insufficiency is a risk factor and endotype of sepsis - A proof-of-concept study to support a precision medicine approach to guide glucocorticoid therapy for sepsis","volume":"13","author":"Wu","year":"2022","journal-title":"Front Immunol"},{"key":"B9","article-title":"Relative adrenal insufficiency is a risk factor for pediatric sepsis - a proof-of-concept study","volume":"229","author":"Hao","year":"2023","journal-title":"J Infect Dis"},{"key":"B10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/s41590-023-01660-5","article-title":"The pathophysiology of sepsis and precision-medicine-based immunotherapy","volume":"25","author":"Giamarellos-Bourboulis","year":"2024","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1097\/TA.0000000000003029","article-title":"Distinct immunologic endotypes are associated with clinical trajectory after severe blunt trauma and hemorrhagic shock","volume":"90","author":"Brakenridge","year":"2021","journal-title":"J Trauma Acute Care Surg"},{"key":"B12","article-title":"Stress hormones in psychophysiological research: emotional, behavioral, and cognitive implications","volume-title":"Handbook of psychophysiology, 4th ed. 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