Cell type-specific regulation of the pentose phosphate pathway during development and metabolic stress-driven autoimmune diseases: Relevance for inflammatory liver, renal, endocrine, cardiovascular and neurobehavioral comorbidities, carcinogenesis, and aging.

The pathogenesis of autoimmunity is incompletely understood which limits the development of effective therapies. New compelling evidence indicates that the pentose phosphate pathway (PPP) profoundly regulate lineage development in the immune system that are influenced by genetic and environmental factors during metabolic stress underlying the development of autoimmunity. The PPP provides two unique metabolites, ribose 5-phosphate for nucleotide biosynthesis in support of cell proliferation and NADPH for protection against oxidative stress. The PPP operates two separate branches, oxidative (OxPPP) and non-oxidative (NOxPPP). While the OxPPP functions in all organisms, the NOxPPP reflects adaptation to niche-specific metabolic requirements. The OxPPP primarily depends on glucose 6-phosphate dehydrogenase (G6PD), whereas transaldolase (TAL) controls the rate and directionality of metabolic flux though the NOxPPP. G6PD is essential for normal development but its partial deficiency protects from malaria. Although men and mice lacking TAL develop normally, they exhibit liver cirrhosis progressing to hepatocellular carcinoma. Mechanistic target of rapamycin-dependent loss of paraoxonase 1 drives autoimmunity and cirrhosis in TAL deficiency, while hepatocarcinogenesis hinges on polyol pathway activation via aldose reductase (AR). Accumulated polyols, such as erythritol, xylitol, and sorbitol, which are commonly used as non-caloric sweeteners, may act as pro-inflammatory oncometabolites under metabolic stress, such as TAL deficiency. The TAL/AR axis is identified as a checkpoint of pathogenesis and target for treatment of metabolic stress-driven systemic autoimmunity with relevance for inflammatory liver, renal and cardiovascular disorders, diabetes, carcinogenesis, and aging.