Bazi Bushen Capsule Rescues Menopausal Obesity–Induced Cognitive Impairment by Restoring AhR–miR-23a-Dependent Mitochondrial Bioenergetics

Postmenopausal women with obesity are at a significantly elevated risk of cognitive impairment. There is therefore an urgent need to uncover the underlying mechanisms of this impairment and develop effective therapeutic strategies. In this study, we demonstrated that treatment with the traditional Chinese herbal formulation Bazi Bushen capsule (BZBS; 1.4 and 2.8 g∙kg –1 ∙d –1 ) significantly alleviated cognitive deficits and restored hippocampal theta rhythm power and frequency in ovariectomized (OVX) high-fat diet-fed (OXHF) mice. Furthermore, we showed that BZBS improved mitochondrial function in the hippocampus, as evidenced by mitochondrial crista structure restoration, decreased reactive oxygen species (ROS) accumulation, and reduced adenosine triphosphate (ATP) depletion. By integrating bioinformatic, molecular, and neurophysiological methods, we found that BZBS inhibited the aryl hydrocarbon receptor (AhR)– miR-23a axis, which reactivated both the nicotinamide phosphoribosyltransferase (NAMPT)–nicotinamide adenine dinucleotide (NAD + )–sirtuin 1 (SIRT1) and proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)–SIRT3 pathways, thus restoring mitochondrial function and increasing ATP levels. This study mechanistically validated the Qi-replenishing bioactivity of BZBS, which aligned with its therapeutic mechanism as informed by traditional Chinese medicine theory. Our findings identified BZBS as a promising therapeutic candidate for alleviating cognitive decline induced by menopausal obesity. Moreover, by elucidating the mechanisms of BZBS at the molecular level, we established a crucial foundation for the clinical use of this Chinese herbal medicine.