biostudies-literatureWang RNational Natural Science Foundation of China5984https://www.ebi.ac.uk/biostudies/studies/S-EPMC10522591biostudies-literatureUnknown14(1)Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamusNature communicationsNatural product P57 induces hypothermia through targeting pyridoxal kinase.PMC105225918162502222031011216210023190073892253305Pei CMa QZhu YFu XWang GJiang MWang JLiang CWang RJiang WBao GGong LXia CMa DKLiu JYWang YDang YWang ZTong QTan MHe MLuo CZhu DLi WZhu MPan JLi ZXiao LYu BHu JLi TfalseNatural product P57 induces hypothermia through targeting pyridoxal kinase.Induction of hypothermia during hibernation/torpor enables certain mammals to survive under extreme environmental conditions. However, pharmacological induction of hypothermia in most mammals remains a huge challenge. Here we show that a natural product P57 promptly induces hypothermia and decreases energy expenditure in mice. Mechanistically, P57 inhibits the kinase activity of pyridoxal kinase (PDXK), a key metabolic enzyme of vitamin B6 catalyzing phosphorylation of pyridoxal (PL), resulting in the accumulation of PL in hypothalamus to cause hypothermia. The hypothermia induced by P57 is significantly blunted in the mice with knockout of PDXK in the preoptic area (POA) of hypothalamus. We further found that P57 and PL have consistent effects on gene expression regulation in hypothalamus2023-01-01T00:00:00Z2023 Sep2025-04-04T08:23:48.244Z2025-04-04T08:23:48.244ZS-EPMC105225913775210610.1038/s41467-023-41435-y