Abstract Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, cachexia-associated metabolites and oncometabolites can accumulate in cancer patients. This study focused on genetic mutations-mediated metabolic reprogramming on cancer cachexia progression by screening for active metabolites and examined their direct effect on muscle atrophy. A total of 157 cachexia-associated metabolites and oncometabolites were selected based on literature collation, and 19 metabolites were screened with in vitro myotube differentiation model. D-2-hydroxyglutarate (D2HG) treatment led to a shorter myotube width and increased mRNA expression of E3 ubiquitin ligases Trim63 and Fbxo32, as well as distinct transcriptional and metabolic changes. Then, we collected 149 cancer patients and confirmed Isocitrate Dehydrogenase 1 (IDH1) mutation in 19 patients with higher D2HG than non-mutational patients. Moreover, 8 cancer patients with IDH1 mutation and cachexia syndrome had higher D2HG. Mutated IDH1 (R132H) in the CT26 cancer cells accelerated cachexia progression (cachexia first occurred at DPI 17 in mice bearing wild-type CT26 tumor vs DPI 22 with mutational IDH1 CT26 tumor) and worsened the overall survival in the murine cancer cachexia model. E3 ligase Trim63 and Fbxo32 were increased by 2.3 and 1.4 times in muscle gastrocnemius of mice bearing CT26 tumor, while mice bearing CT26 tumor with mutational IDH1 increased 3.4 and 2.3 times respectively. Furthermore, overexpressed D-2-hydroxyglutarate dehydrogenase (D2hgdh) in well-differentiated myotubes alleviated 93µM D2HG induced shorter myotube width and upregulated E3 ligases. Transcriptomics and metabolomics revealed a distinct D2HG induced metabolic disequilibrium. Additionally, IDH1 inhibitor ivosidenib treatment delayed the progression of cancer cachexia in murine cancer model bearing CT26 colon carcinoma and GL261 glioma cancer cells. In the cachexia model of mice bearing CT26 tumor, ivosidenib decreased 58.5% serum D2HG concentration, preserved 15.1% muscle gastrocnemius mass and 11.9% lean body weight, improved 35.6% area of muscle gastrocnemius, and inhibited the unregulated mRNA expression of Ube2d1, Trim63 and Fbxo32, when compared with NTC treated mice bearing CT26 tumor with IDH1 mutation. These results indicated the contribution of IDH1 mutation in mediating excessive D2HG accumulation in cancer cachexia progression and highlighted the possibility of individualized treatment for patients with cancer cachexia with an IDH1 mutation.