Molecular mechanisms of cellular control through the TXNIP protein

The thioredoxin-interacting protein (TXNIP) is a unique member of the a-arrestin family, as it is the only arrestin identified as an endogenous inhibitor of thioredoxin (TRX). TRX is a small 12-kDa protein that functions as an antioxidant by reducing disulfide bonds in target proteins to maintain their activity, thus regulating the cellular redox (reduction and oxidation) environment. Even though in vitro systems showed that TXNIP inhibited TRX activity, the cellular interplay between TXNIP and TRX remains unclear under physiological conditions as genetic deletions of TXNIP in animals did not change TRX activity. Several studies have demonstrated that some of the metabolic functions of TXNIP do not depend on inhibition of TRX, but are instead similar to those of other closely related a- arrestins, such as arrestin domain-containing protein 4 (Arrdc4). As inhibiting TXNIP is being explored as a therapeutic target for diabetes, studying the metabolic adaptation of TXNIP deficiency using patient-derived primary cells provides translational insights for potential future clinical applications. In Paper I, we identified a mechanism underlying NRF2 activation in patient- derived primary cells. Our results suggest that enhanced glucose uptake and glycolysis driven by TXNIP loss result in the accumulation of the highly reactive and harmful metabolite methylglyoxal (MGO), accompanied by increased levels of glyoxalase 1 (GLO1). MGO modifies KEAP1, which releases NRF2 and activates the NRF2 pathway. This finding resolves a previously puzzling contradiction: given that TXNIP is a TRX inhibitor, TXNIP deficiency would be expected to create a more reducing intracellular environment that suppresses NRF2 rather than activating it. In Paper II, we investigated the cellular interplay between TXNIP and TRX using two different cellular models: patient-derived TXNIP-deficient primary cells and doxycycline-inducible TRX knockdown Hela cells. Our findings challenge the traditional view that TXNIP primarily functions as an inhibitor of TRX and instead suggest that TRX regulates TXNIP-driven glucose signalling. We further provide a mechanistic explanation for the increased lactate production commonly reported upon TXNIP loss. Specifically, TXNIP suppresses PGC-la, a positive regulator of PDK4 transcription, thereby limiting PDK4-mediated inhibitory phosphorylation of PDHC and maintaining PDHC activity. In the absence of TXNIP, elevated PGC-la increases PDK4 expression, which phosphorylates and inactivates PDHC. Consequently, pyruvate is redirected towards lactate production in the cytosol instead of complete mitochondrial oxidation, promoting a glycolytic shift. List of scientific papers I. Maimaiti Shayida, Dagnell Markus, Coppo Lucia, Arner S.J. Elias. TXNIP-deficient primary cells exhibit NRF2 activation linked to upregulation of glyoxalase 1 (GLO1). Free Radic Biol Med. 2025 Jul 26;239:230-241. PMID: 40721014. https://doi.org/10.1016/j.freeradbiomed.2025.07.035 II. Maimaiti Shayida, Dagnell Markus, Coppo Lucia, Zhao Wenchao, Geserick Peter, Kappert Kai, Arner S.J. Elias. Thioredoxin 1 supresses TXNIP-driven control of glucose metabolism in human cells. Antioxidant and Redox Signaling. 2026 Feb 24. PMID: 41736403. https://doi.org/10.1177/15230864261421616