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

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.

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.

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).

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).

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.