d‐Sorbose Promotes Regulatory T‐Cell Differentiation and Ameliorates Autoimmune and Allergic Diseases via Hexosamine Biosynthetic Pathway Inhibition

ABSTRACT Monosaccharides are fundamental biomolecules involved in various biological processes. Rare sugars, naturally scarce monosaccharide derivatives, exhibit unique physiological effects independent of standard energy metabolism. Among them, d‐sorbose, the C‐3 epimer of d‐fructose, has poorly understood biological functions. This study investigated the immunometabolic effects of d‐sorbose, focusing on regulatory T‐cell (Treg) differentiation and immune modulation. Ex vivo assays using splenic naïve CD4 + T cells revealed that d‐sorbose significantly increased Foxp3 + Treg frequencies to levels comparable to d‐mannose, without inducing the CD8 + T cell reduction observed with d‐mannose. In vivo, continuous d‐sorbose administration ameliorated ovalbumin‐induced airway inflammation and prevented autoimmune diabetes in non‐obese diabetic mice by selectively increasing interleukin‐10‐producing Tregs in regional lymph nodes and inflamed tissues. Histological analyses revealed reduced inflammatory cell infiltration and preserved tissue architecture in d‐sorbose‐treated groups. Metabolomic profiling indicated that d‐sorbose suppressed glycolysis, the pentose phosphate pathway, and the hexosamine biosynthetic pathway (HBP), as evidenced by decreased UDP‐GlcNAc levels, while elevating the tricarboxylic acid cycle intermediate malate. Pharmacological inhibition of glutamine–fructose‐6‐phosphate aminotransferase, combined with glutamine restriction and GlcNAc rescue assays, demonstrated that d‐sorbose promotes Treg differentiation through coordinated metabolic reprogramming of glucose partitioning and glutamine catabolism rather than passive HBP inhibition. Notably, d‐sorbose treatment did not alter T‐cell survival and demonstrated a favorable safety profile during long‐term administration. These findings identify d‐sorbose as a novel immunoregulatory sugar that promotes functional Treg differentiation by orchestrating intracellular glucose and glutamine metabolism, highlighting its potential as a dietary or therapeutic agent for controlling inflammatory and autoimmune diseases.