Reprogramming the impact of glutamine metabolism on controlling the immunoinflammatory milieu in psoriasis

Psoriasis is a chronic, systemic inflammatory immune disorder typically characterised by the formation of well-demarcated scaly erythematous plaques and epidermal hyperkeratosis. Metabolic reprogramming, an interdisciplinary paradigm of pathological mechanisms and a target of translational medicine, has been shown to play a multilevel biological role in the study of psoriasis, particularly in its pathological microenvironment, where glutamine, a nitrogen-carbon bifunctional donor, acts as a biosynthetic precursor to the formation of plaques in keratinocytes (KCs) in addition to providing adenosine triphosphate (ATP) energy for the aberrant proliferation of KCs through the catabolism of α-ketoglutarate (α-KG). In addition to acting as biosynthetic precursors and supplying carbon skeletons and amino acid donors for nucleotide, membrane phospholipid, and amino acid synthesis, metabolic intermediates supply ATP to sustain aberrant KC proliferation. Metabolic intermediates also trigger inflammatory signalling pathways that are intimately linked to psoriasis, including mammalian target of rapamycin protein (mTOR), nuclear transcription factor kappa B (NF-κB), and signal transducer and activator of transcription 3 (STAT3). Psoriatic inflammation can be effectively reduced by inhibiting essential proteins and enzymes involved in glutamine metabolism. The establishment of a 'metabolic checkpoint-immune microenvironment' dynamic intervention strategy involving the aforementioned mechanisms is creatively proposed in this paper. This strategy offers a theoretical foundation for the development of metabolic homeostasis-based precision therapy, particularly for refractory patients who do not adequately respond to traditional biologics.