Valerenic acid attenuates chronic stress-exacerbated metabolic dysfunction-associated steatotic liver disease via the estrogen receptor α-GDF15 axis

Abstract

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been rising annually. Meanwhile, with intensifying societal pressure, there has been a parallel surge in the prevalence of psychological disorders. The coexistence of these conditions creates a complex comorbidity, leading to heightened metabolic and cardiovascular risks, and posing challenges to traditional therapeutic approaches. Valerenic acid, a natural compound derived from the roots of Valeriana officinalis, exhibits sedative, anxiolytic, anti-inflammatory, and antioxidant effects, which may offer a promising therapeutic intervention for MASLD complicated by stress. The present study aims to experimentally evaluate the therapeutic effects of valerenic acid as well as to explore its pharmacological mechanisms, thereby providing evidence for its clinical application. Both male and female C57BL/6J mice were utilized in this study. A Western diet was employed to induce MASLD, while moderate, intermittent, and prolonged restraint stress was applied to simulate chronic stress, whereas valerenic acid was orally gavaged to assess its therapeutic efficacy. The outcomes revealed that, in both sexes, the initial phase of restraint stress induced concurrent reductions in food intake and body weight; however, following an adaptation period, persistent chronic stress paradoxically resulted in escalation of both food consumption and weight gain. Intervention with valerenic acid effectively attenuated stress-induced fluctuations in feeding behavior and body weight. Furthermore, estrogen receptor α was identified as a key target of valerenic acid, which regulated the pivotal immunometabolic mediator growth differentiation factor 15, thereby suppressing appetite while ameliorating hepatic inflammatory pathology.