Structure-activity relationships and molecular mechanisms of natural products in sepsis-associated organ dysfunction: a narrative review

Background: 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. Problem: 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. Methods: 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). Results: Evidence reveals that specific structural features-such as functional group substitutions, spatial ring conformations, and quaternary ammonium charge states-directly 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-κB/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). Conclusion: 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.