Mechanism of LEPR-mediated cholesterol metabolism involved in NK cell function suppression under simulated microgravity

Natural killer (NK) cells play an important role in antitumor and viral resistance. However, the mechanism of impaired NK cell function in microgravity remains unclear. Cholesterol metabolism, a new research hotspot, plays a critical role in NK cells function. This study found that simulated microgravity downregulate NK cell membrane cholesterol levels by disrupting cholesterol biosynthesis and transport to the membrane, leading to the obstruction of activated immune synapse formation, which inhibit the release of NK cell cytotoxic particles and ultimately decreasing NK cell immune function. Most importantly, this study identified a new target for regulating NK cell function, LEPR (leptin receptor). LEPR affected NK cell membrane cholesterol levels by influencing the CAMKK–SREBP1–HMGCR cholesterol endogenous synthesis pathway and regulating the expression of NPC1 and NPC2 genes, which ultimately influencing NK cell cytotoxic function. The study is significant for understanding the mechanism of NK cell activity in microgravity and offers new targets for clinical immunotherapy of NK cells.