DIO3 (iodothyronine deiodinase 3) is a selenoprotein 1 that catalyzes the inactivation of thyroid hormones through inner-ring deiodination, converting T4 to reverse T3 and T3 to 3,3'-T2, among other substrates 2345. The enzyme also performs outer-ring deiodination and acts on iodothyronamines 56. DIO3 is paternally expressed within the imprinted Dlk1-Dio3 cluster on chromosome 14, a domain critical for development and postnatal metabolism 78. Dysregulation of this imprinted region causes Temple syndrome (maternal UPD14) or Kagami-Ogata syndrome (paternal UPD14) 7. Expression is controlled by a bipartite imprinting control region, with selective loss of imprinting in the neurogenic niche 9. DIO3 functions as a developmental timer: high expression in retinal progenitor cells suppresses thyroid hormone signaling, while progressive downregulation during differentiation increases signaling to specify photoreceptor subtypes 10. In skeletal muscle during sepsis, DIO3-mediated thyroid hormone inactivation impairs mitophagy and anabolic processes; Dio3 knockdown preserves muscle mass via NAD salvage pathway activation 11. Dio3os lncRNA regulates neighboring Dio3 expression and impacts osteogenesis, with aberrant Dio3 expression causing consumptive hypothyroidism and skeletal developmental abnormalities 12.