{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T05:59:58Z","timestamp":1780898398496,"version":"3.54.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The seroconversion of hepatitis B e antigen (HBeAg) remains difficult to be completely obtained in the treatment of hepatitis B. This study aimed to characterize the metabolic signatures of HBeAg-positive patients and identify key metabolites associated with HBeAg seroconversion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Untargeted metabolomic analysis was conducted to investigate the plasma metabolic profiles of HBeAg-positive (n=54) and negative (n=33) patients. Subgroup analyses were performed in patients with persistent HBeAg&amp;lt;20IU\/ml level (n=33) versus those with HBeAg-negative (n=33) and patients with immune tolerant (n=8) versus immune active phases (n=7). Targeted metabolomic analysis was used to validate specific amino acids in an external cohort (n=90). The biological effects of gamma-glutamylglycine were examined by\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with patients who achieved HBeAg seroconversion, HBeAg-positive patients exhibited distinct metabolic profiles, with 227 differential metabolites (133 downregulated and 94 upregulated, P&amp;lt;0.05). KEGG pathway enrichment analysis revealed downregulated tryptophan, pyruvate, glycine, serine, and threonine metabolism, and glycerophospholipid metabolism and upregulated arginine biosynthesis, and cysteine and methionine metabolism in HBeAg-positive patients (P&amp;lt;0.01). Gamma-glutamylglycine and Na-L-glutamyl-aspartic acid were significantly upregulated in HBeAg-positive patients by both untargeted and targeted metabolomic analysis (P&amp;lt;0.05). Furthermore, a predictive model integrating plasma gamma-glutamylglycine accurately identified HBeAg seroconversion in both developing (AUC\u00a0=\u00a00.857, 95% CI: 0.765-0.923) and external (AUC\u00a0=\u00a00.780, 95% CI: 0.680-0.861) cohorts.\n                      <jats:italic>In vitro<\/jats:italic>\n                      assays showed that gamma-glutamylglycine contributed to the production of HBeAg in HBV-replicating cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Altered amino acid metabolism is a predominant metabolic feature of HBeAg-positive patients and plasma levels of gamma-glutamylglycine are negatively associated with HBeAg seroconversion.<\/jats:p>\n                  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