DIO3 is a selenoprotein that catalyzes the inactivation of thyroid hormones through inner-ring and outer-ring deiodination reactions. It converts thyroxine (T4) to reverse T3 (rT3) and degrades active T3 to less bioactive metabolites, thereby regulating local thyroid hormone signaling. The gene is paternally expressed as part of the imprinted Dlk1-Dio3 cluster on chromosome 14, and dysregulation of this domain causes Temple and Kagami-Ogata syndromes, which present with developmental and metabolic abnormalities. Recent evidence suggests DIO3 has tissue-specific roles beyond hormone metabolism: in retinal development, high DIO3 expression in progenitor cells suppresses thyroid hormone signaling to delay photoreceptor differentiation, and DIO3 knockdown promotes precocious cone and rod development 1. In skeletal muscle during sepsis, DIO3-mediated local hypothyroidism impairs mitophagy and promotes muscle wasting; DIO3 inhibition restores NAD-dependent mitochondrial quality control and preserves muscle mass 2. Aberrant DIO3 expression in consumptive hypothyroidism disrupts skeletal development through thyroid hormone inactivation 3. The Dlk1-Dio3 cluster is also dysregulated in systemic lupus erythematosus and urological cancers, where imprinted microRNAs contribute to disease pathogenesis. These findings identify DIO3 as a therapeutic target for sepsis-induced wasting and skeletal disorders through modulation of local thyroid hormone metabolism.