Sulfated polysaccharides from sea cucumber mitigate acetaminophen-induced acute liver injury in mice via citraconic acid-mediated inhibition of oxidative stress.

Acetaminophen (APAP) is a widely used antipyretic and analgesic drug, but excessive or prolonged use can cause liver injury. Sulfated polysaccharides from sea cucumber (SCSP) exhibit diverse bioactivities; however, their protective role against APAP hepatotoxicity remains unclear. Here, SCSP pretreatment significantly alleviated APAP-induced liver injury in mice, as evidenced by reduced hepatic necrosis, serum transaminases, inflammation, and oxidative stress. 16S rRNA sequencing revealed that SCSP preserved gut microbial diversity and enriched beneficial bacterial taxa, partially counteracting APAP-induced dysbiosis. Metabolomics analysis further demonstrated that SCSP remodeled microbiota metabolic outputs and mitigated APAP-induced serum metabolic abnormalities, particularly in amino acid metabolism. Notably, citraconic acid (CA) was identified as a key metabolite restored by SCSP and strongly associated with improved hepatic outcomes, with concordant changes observed between gut and serum. Functional validation confirmed that CA pretreatment protected against APAP-induced liver injury by enhancing antioxidative defenses and reducing inflammatory responses. In vitro, CA reduced oxidative damage and activated the Nrf2 pathway. Collectively, these results support SCSP as a promising preventive prebiotic that enhances hepatic resilience to APAP challenge via modulation of the gut-liver axis, with CA representing an important mechanistic mediator.