ALKBH7 is a mitochondrial RNA demethylase that regulates mitochondrial gene expression through removal of N2,N2-dimethylguanosine (m22G) and N1-methyladenosine (m1A) from nascent polycistronic mitochondrial pre-tRNA regions 1. This demethylation activity controls the processing and structural dynamics of mitochondrial RNA, influencing steady-state tRNA levels, protein translation, and overall mitochondrial activity 1. ALKBH7 possesses a conserved iron-coordinating double-stranded β-helix fold characteristic of α-ketoglutarate-dependent dioxygenases, but uniquely lacks the nucleotide-recognition domains found in other AlkB family members, suggesting potential protein substrate specificity 2. Beyond its RNA demethylase function, ALKBH7 plays a critical role in programmed necrosis induced by DNA damage. Following severe alkylation or oxidative stress, ALKBH7 triggers mitochondrial membrane potential collapse and loss of mitochondrial function, leading to NAD+ and ATP depletion and subsequent cell death 3. This response exhibits tissue and sex-specific patterns, with male organisms showing enhanced sensitivity 4. Depletion of ALKBH7 suppresses necrotic cell death while maintaining mitochondrial bioenergetics 3, making it a potential therapeutic target for diseases involving excessive cell death. Clinically, ALKBH7 dysregulation associates with inflammatory diseases and cancer. HIF-1α-mediated ALKBH7 downregulation drives mitochondrial damage and fibroblast activation in rheumatoid arthritis 5, while ALKBH7-NLRP3 co-expression correlates with breast cancer aggressiveness and immunometabolic profiles 6.