ETHE1 (ETHE1 persulfide dioxygenase) is a mitochondrial sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism by oxidizing persulfide substrates to prevent toxic H2S accumulation 1. The enzyme catalyzes the dioxygenation of glutathione persulfide to glutathione and sulfite, working downstream of SQRDL in the sulfide oxidation pathway 2. ETHE1 contains a mononuclear iron active site with a 2-His/1-Asp ligand set and requires direct substrate binding to prime the site for oxygen activation 1. Beyond its metabolic function, ETHE1 has diverse roles in cancer biology, including inhibiting angiogenesis in colorectal cancer by promoting STAT3 dephosphorylation and reducing VEGF-A expression 3, and paradoxically promoting metastasis in triple-negative breast cancer through GCN2/eIF2α/ATF4 signaling activation 4. ETHE1 deficiency causes ethylmalonic encephalopathy, a rare autosomal recessive disorder characterized by developmental delay, seizures, and microvascular damage presenting with petechiae and purpura that can mimic meningococcemia 5. Patient fibroblasts show disrupted mitochondrial bioenergetics, increased superoxide production, and impaired ER-mitochondria communication 6, highlighting ETHE1's critical role in cellular homeostasis.