biostudies-literatureTabata SMEXT | Japan Society for the Promotion of ScienceJapan Agency for Medical Research and Developmentresearch funds from the Yamagata Prefecture Government, Japan, and City of Tsuruoka, JapanMEXT | Japan Science and Technology Agency1294-1307https://www.ebi.ac.uk/biostudies/studies/S-EPMC10101855biostudies-literatureUnknown42(16)Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reducedOncogeneL-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis.PMC1010185522K0715017KK0199JPMJCR2123JP18gm0710003JP21zf0127001Aoki MIshikawa TSoga TSakamoto NKajino-Sakamoto RUmetsu KTabata SHirayama AIgarashi KYasumoto KIKojima YSuzuki YYachida SOkano KSakamoto TfalseL-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis.Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced2023-01-01T00:00:00Z2023 Apr2026-07-14T19:10:46.765Z2025-04-04T23:00:38.473ZS-EPMC101018553687911710.1038/s41388-023-02632-7