Quercetin-3-β-aminobutyrate (HPS-β) as a promising novel anti-inflammatory agent for the treatment of sepsis.

Sepsis is a life-threatening condition characterized by excessive inflammatory responses and oxidative stress, leading to organ dysfunction, high mortality, and morbidity. Quercetin, a natural flavonoid with anti-inflammatory and antioxidant properties, has limited clinical application due to its poor solubility and bioavailability. To address these limitations, we designed and synthesized a novel quercetin β-aminobutyrate derivative, Quercetin-3-β-aminobutyrate (HPS-β), using a prodrug strategy. HPS-β demonstrated a 17,500-fold increase in phosphate buffer solubility and significantly improved bioavailability compared to quercetin. In vitro studies revealed that HPS-β effectively suppressed macrophage activation, reduced the release of proinflammatory cytokines (IL-6 and TNF-α), and mitigated reactive oxygen species (ROS) production in LPS-induced RAW264.7 cells. In vivo experiments using LPS-induced septic mice showed that HPS-β improved survival rates, lowered serum levels of inflammatory cytokines, and ameliorated sepsis-related lung injury and the disruption of intestinal barrier integrity. Importantly, HPS-β exhibited no apparent toxicity to major organs. Mechanistically, HPS-β exerted its therapeutic effects by inhibiting oxidative stress and reducing inflammatory cytokine release. These findings highlight HPS-β as a promising therapeutic candidate for sepsis treatment, offering improved solubility, bioavailability, and efficacy compared to quercetin.