The incidence of precocious puberty (PP, the appearance of signs of pubertal development at an abnormally early age), is rapidly rising, concurrent with changes of diet, lifestyles, and social environment. The current diagnostic methods are based on a hormone (gonadotropin-releasing hormone) stimulation test, which is costly, time-consuming, and uncomfortable for patients. The lack of molecular biomarkers to support simple laboratory tests, such as a blood or urine test, has been a long standing bottleneck in the clinical diagnosis and evaluation of PP. Here we report a metabolomic study using an ultra performance liquid chromatography-quadrupole time of flight mass spectrometry and gas chromatography-time of flight mass spectrometry. Urine metabolites from 163 individuals were profiled, and the metabolic alterations were analyzed after treatment of central precocious puberty (CPP) with triptorelin depot. A panel of biomarkers selected from >70 differentially expressed urinary metabolites by receiver operating characteristic and logistic regression analysis provided excellent predictive power with high sensitivity and specificity for PP. The altered metabolic profile of the PP patients was characterized by three major perturbed metabolic pathways: catecholamine, serotonin metabolism, and tricarboxylic acid cycle, presumably resulting from activation of the sympathetic nervous system and the hypothalamic-pituitary-gonadal axis. Treatment with triptorelin depot was able to normalize these three altered pathways. Additionally, significant changes in the urine levels of 4-hydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, indoleacetic acid, 5-hydroxytryptophan, and 5-hydroxykynurenamine in the CPP group suggest that the development of CPP condition may involve an alteration in symbiotic gut microbial composition.

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy with poor prognosis. Rising incidence of HCC may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development. Thirty-five bile acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays in pre-diagnostic serum of 100 HCC cases and 100 matched controls from the Singapore Chinese Health Study. Conditional logistic regression was used to assess associations for bile acid levels with risk of HCC. Conjugated primary bile acids were significantly elevated whereas the ratios of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls. The respective odds ratios and 95% confidence intervals of HCC were 6.09 (1.75–21.21) for highest vs. lowest tertile of cholic acid species and 30.11 (5.88–154.31) for chenodeoxycholic acid species. Doubling ratio of taurine-over glycine-conjugated chenodeoxycholic acid was associated significantly with 40% increased risk of HCC whereas doubling ratio of secondary over primary bile acid species was associated with 30–40% reduced risk of HCC. In conclusion, elevated primary bile acids and taurine over glycine-conjugated ratios were strongly associated with HCC risk whereas the ratios of secondary bile acids over primary bile acids were inversely associated with HCC risk.

Metabolites in the tumor microenvironment are a critical factor for tumor progression. However, the lack of knowledge about the metabolic profile in the bone marrow (BM) microenvironment of multiple myeloma (MM) limits our understanding of MM progression. Here, we show that the glycine concentration in the BM microenvironment is elevated due to bone collagen degradation mediated by MM cell-secreted matrix metallopeptidase 13 (MMP13), while the elevated glycine level is linked to MM progression. MM cells utilize the channel protein solute carrier family 6 member 9 (SLC6A9) to absorb extrinsic glycine subsequently involved in the synthesis of glutathione (GSH) and purines. Inhibiting glycine utilization via SLC6A9 knockdown or the treatment with betaine suppresses MM cell proliferation and enhances the effects of bortezomib on MM cells. Together, we identify glycine as a key metabolic regulator of MM, unveil molecular mechanisms governing MM progression, and provide a promising therapeutic strategy for MM treatment.