Liquiritigenin attenuates high-salt diet-induced neuroinflammation, mitochondrial dysfunction, and cognitive impairment via NF-κB pathway inhibition.

Liquiritigenin (LG), a flavonoid compound extracted from licorice, possesses diverse pharmacological activities, including anti-inflammatory and antioxidant effects. A high-salt diet (HSD) is a common dietary risk factor associated not only with hypertension but also with central nervous system injury. However, the underlying mechanisms and potential therapeutic interventions remain insufficiently explored. In this study, we investigated the neuroprotective effects of LG against HSD-induced brain pathology and cognitive impairment in mice. The mechanism of action was further examined using NaCl-treated HT22 cells with LG intervention. By establishing HSD-related mouse and cellular models, administering different doses of LG, and performing neurobehavioral assessments, we evaluated its effects on brain tissue structure, cognitive performance, neuroinflammation, and mitochondrial function. The results demonstrated that in HSD-fed mice, LG attenuated hippocampal neuronal atrophy and death, thereby improving brain tissue morphology. Behavioral testing further revealed that LG enhanced motor performance and exploratory behavior, alleviating cognitive deficits. At the molecular level, LG reduced the expression of pro-inflammatory mediators while upregulating anti-inflammatory cytokines, effectively suppressing neuroinflammation. In addition, LG decreased cytoplasmic expression of mitochondrial DNA-related genes (d-loop, cox1, non-numt), increased ATP production, and improved mitochondrial function. Mechanistic studies further indicated that LG inhibits HSD-induced nuclear factor kappa-B p65 phosphorylation, reducing neuroinflammation and mitochondrial dysfunction, whereas NF-κB p65 overexpression abrogated these protective effects. In summary, LG protects against neuroinflammation and mitochondrial impairment by suppressing NF-κB signaling, thereby mitigating neurological dysfunction. These findings suggest that LG holds promise as a potential therapeutic agent for the prevention and treatment of HSD-related neurological disorders.