Txnrd1, or thioredoxin reductase 1, is a key selenoprotein in the thioredoxin (TXN) system, an NADPH + H+/FAD redox-triggered effector. It is crucial for maintaining cellular redox homeostasis, which is essential for bioenergetics, detoxifying drug networks, and cell survival in oxidative stress-related conditions [3]. It is also involved in various cellular processes such as cell proliferation, apoptosis, and the innate immune response [2,5].

In osteoclast precursors, inhibition of Txnrd1 leads to increased cystine transport, disulfide stress, and disulfidptosis, reducing osteoclast numbers and alleviating bone loss in an ovariectomized mouse model, suggesting its role in bone metabolic diseases [1]. In senescent cells, Txnrd1 drives the senescence-associated secretory phenotype (SASP) and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway, independently of its enzymatic activity, and its inhibitor can downregulate markers of inflammaging in aged mice [2]. In hepatocellular carcinoma (HCC), SLC27A5 deficiency activates the NRF2/Txnrd1 pathway, and blockade of this pathway sensitizes SLC27A5-deficient hepatoma cells to sorafenib treatment [4]. In endothelial cells under oscillatory shear stress, knockdown of Txnrd1 inhibits cell proliferation by activating the endothelial nitric oxide synthase/apoptosis pathway, indicating its involvement in atherosclerosis [5]. In osteoarthritis, inhibition of Txnrd1 in chondrocytes can prevent cartilage extracellular matrix degeneration by activating the Nrf2 pathway [6].

In conclusion, Txnrd1 is essential for maintaining cellular redox balance and is involved in multiple biological processes. Studies using gene-targeted mouse models (such as in the context of osteoporosis, aging-related inflammation, HCC, atherosclerosis, and osteoarthritis) have revealed its significance in these disease conditions, providing potential therapeutic targets for related diseases.