Quercetin promotes the proliferation and maturation of NK cells by binding to MYH9 and improves cognitive functions in aged mice

<title>Abstract</title> <bold>Background: </bold>Quercetin is a flavonol compound widely distributed in plants that possesses diverse biological properties, including antioxidative, anti-inflammatory, anticancer, neuroprotective and senescent cell-clearing activities. It has been shown to effectively alleviate neurodegenerative diseases and enhance cognitive functions in various models. The immune system has been implicated in the regulation of brain function and cognitive abilities. However, it remains unclear whether quercetin enhances cognitive functions by interacting with the immune system. <bold>Results: </bold>In this study, middle-aged female mice were administered quercetin <italic>via</italic> tail vein injection. Quercetin increased the proportion of NK cells, without affecting T or B cells, and improved cognitive performance. Depletion of NK cells significantly reduces cognitive ability in mice. RNA-seq analysis revealed that quercetin modulated the RNA profile of hippocampal tissues in aging animals towards a more youthful state. <italic>In vitro</italic>, quercetin significantly inhibited the differentiation of Lin⁻CD117⁺ hematopoietic stem cells into NK cells. Furthermore, quercetin promoted the proliferation and maturation of NK cells by binding to the MYH9 protein. <bold>Conclusions: </bold>In summary, our findings suggest that quercetin promotes the proliferation and maturation of NK cells by binding to the MYH9 protein, thereby improving cognitive performance in middle-aged mice.