Patient-derived TXNIP-deficient primary cells exhibit NRF2 activation linked to upregulation of glyoxalase 1 (GLO1)

Thioredoxin-interacting protein (TXNIP) plays a pivotal role in cellular redox regulation and has been implicated in various pathological conditions, including oxidative stress, inflammation and metabolic disorders including diabetes. In this study, we investigated the metabolic consequences of TXNIP deficiency in patient-derived primary cells, with a particular focus on molecular mechanisms by which TXNIP loss may trigger the NRF2 activation noted in these cells. Studying primary TXNIP deficient myoblasts and fibroblasts, we found altered expression levels of NOX2 and NOX4, but no overt increase in hydrogen peroxide levels, nor obvious perturbations in levels of the transsulfuration enzymes CBS and CSE. Baseline activation of NRF2 was however associated with upregulation of glyoxalase 1 (GLO1), a key enzyme responsible for detoxifying the reactive glucose metabolite methylglyoxal (MGO). The upregulation of GLO1 also led to increased production of D-Lactate in TXNIP deficient fibroblasts, a downstream product of MGO detoxification, suggesting an imbalance in glycolytic flux with increased MGO production, in turn activating NRF2. Rewiring of intracellular glucose metabolism can thus provide a mechanistic explanation for how TXNIP deficiency leads to NRF2 activation in absence of detectable oxidative stress. Considering that TXNIP inhibition is proposed as a diabetic or anti-inflammatory treatment modality, MGO-derived NRF2 activation should hence be considered as a potential consequence.