Gut Microbiota-Derived Hexanoic Acid Mediates the Protective Effects of Electroacupuncture Against Sepsis Through Macrophage Reprogramming

Abstract Highlights： Electroacupuncture alleviates sepsis-associated liver injury by promoting the gut microbial Lactobacillus vaginalis–hexanoic acid axis. Microbiota-derived hexanoic acid targets BMAL1 to suppress NF-κB-mediated pro-inflammatory macrophage polarization. INT-777-functionalized pH-responsive liposomes enhance the hepatic delivery and therapeutic efficacy of hexanoic acid. Abstract Sepsis-induced liver injury (SLI) is a severe complication of sepsis with limited effective therapeutic options. This study explored the mechanism by which electroacupuncture (EA) protects against SLI and its therapeutic translation through a targeted nanodelivery system. Our findings showed that EA remodeled the gut microbiota, increased the abundance of Lactobacillus vaginalis (L.V), and promoted the production of microbiota-derived hexanoic acid (HA). Mechanistically, HA interacted with BMAL1 and inhibited NF-κB activation, thereby suppressing pro-inflammatory macrophage polarization and alleviating hepatic inflammation and injury. However, the rapid metabolism and limited therapeutic delivery of free HA may restrict its therapeutic application. To overcome these limitations, we developed an INT-777-modified PH-responsive liposomal nanodelivery system (HA@L-INT) to enhance the targeted delivery of HA. HA@L-INT exhibited enhanced hepatic accumulation and superior therapeutic efficacy compared with free HA, resulting in greater suppression of inflammatory macrophage polarization and liver injury. Collectively, the gut microbial L.V–HA axis mediates the protective effects of EA against SLI by regulating macrophage polarization, while targeted nanodelivery further enhances the therapeutic potential of HA.