{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:17:30Z","timestamp":1791580650652,"version":"4.3.4"},"reference-count":133,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T00:00:00Z","timestamp":1775779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite significant advancements in modern life-support technologies, the mortality rate of sepsis and its associated complications in the intensive care unit (ICU) remains unacceptably high.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Problem<\/jats:title>\n                    <jats:p>The repeated clinical failure of traditional single-target therapies (e.g., anti-endotoxin agents) underscores an urgent need for systemic therapeutic strategies capable of simultaneously restoring the immune, metabolic, and coagulation networks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This comprehensive narrative review evaluates the pharmacological mechanisms of natural bioactive compounds in mitigating sepsis-associated organ dysfunction. Unlike previous descriptive reviews, we categorize active compounds based on their core chemical scaffolds (flavonoids, terpenoids, alkaloids, and quinones) and provide a rigorous comparative analysis of their structure-activity relationships (SAR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Evidence reveals that specific structural features\u2014such as functional group substitutions, spatial ring conformations, and quaternary ammonium charge states\u2014directly dictate the pharmacokinetic stability, blood-brain barrier (BBB) penetrability, and intracellular target affinity of these natural products. By leveraging these structural advantages, natural products exert multi-organ protective effects (spanning the lungs, kidneys, heart, liver, intestines, and brain) through the synergistic modulation of three converging hubs: the NF-\u03baB\/NLRP3 inflammatory axis, the Nrf2\/HO-1 antioxidant system, and the AMPK\/mTOR immunometabolic circuit. Specifically, they demonstrate profound efficacy in inhibiting macrophage M1 polarization, blocking neutrophil extracellular trap (NET) formation, ameliorating mitochondrial bioenergetic crises, and alleviating sepsis-associated encephalopathy (SAE).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Although natural products offer profound multi-target advantages, their clinical translation is frequently hindered by poor druggability, unstable pharmacokinetics, and narrow therapeutic windows. Future research must decisively transition from empirical screening to SAR-guided lead optimization, integrating advanced nano-delivery systems and biomarker-driven precision clinical trials to successfully advance these natural scaffolds into clinical applications.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1808772","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T06:05:56Z","timestamp":1775801156000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Structure-activity relationships and molecular mechanisms of natural products in sepsis-associated organ dysfunction: a narrative review"],"prefix":"10.3389","volume":"17","author":[{"given":"Jia","family":"Wang","sequence":"first","affiliation":[{"name":"Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Cai","sequence":"additional","affiliation":[{"name":"Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Liang","sequence":"additional","affiliation":[{"name":"The First Hospital Affiliated to Heilongjiang University of Chinese Medicine","place":["Harbin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1021\/mp700113r","article-title":"Bioavailability of curcumin: problems and promises","volume":"4","author":"Anand","year":"2007","journal-title":"Mol. 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