TXNRD3 is a selenoprotein-containing thioredoxin reductase 1 that functions as a multifunctional oxidoreductase with thioredoxin reductase, glutaredoxin, and glutathione reductase activities. While traditionally characterized for its role in spermatogenesis and sperm maturation through disulfide bond formation 2, TXNRD3 has broader physiological importance in maintaining cellular redox homeostasis across multiple tissues. Mechanistically, TXNRD3 regulates oxidative stress and antioxidant defense systems by modulating reactive oxygen species (ROS) levels and antioxidant enzyme activities including SOD, GSH, and notably GPX4 34. The enzyme is regulated by transcription factors like Foxn1 in keratinocytes, particularly under hypoxic conditions 5. TXNRD3 deficiency promotes multiple pathologies: Txnrd3 knockout mice develop exacerbated liver fibrosis via ferroptosis pathway activation 4, increased colitis severity with enhanced pyroptosis and necrosis 6, and worsened nickel-induced kidney and liver injury 23. Conversely, TXNRD3 overexpression inhibits colon cancer cell proliferation through calcium-dependent mechanisms 6. High TXNRD3 expression associates with poor prognosis in pancreatic cancer and correlates with tumor immune microenvironment characteristics 7. These findings establish TXNRD3 as a critical redox regulator with implications for fibrotic diseases, inflammatory conditions, and cancer biology.