AIFM1 is a mitochondrial flavoprotein that functions as a key mediator of caspase-independent cell death pathways and mitochondrial bioenergetics. The protein localizes primarily to the mitochondrial intermembrane space where it exhibits NADH oxidoreductase activity and plays essential roles in mitochondrial function and biogenesis 1. AIFM1 serves as a central component in multiple cell death pathways, including parthanatos and oxeiptosis. In parthanatos, AIFM1 translocates from mitochondria to the nucleus upon binding to poly(ADP-ribose) polymers, either directly or via the 89-kDa PARP1 cleavage fragment, to induce DNA fragmentation and cell death 2. In oxeiptosis, a ROS-induced caspase-independent pathway, AIFM1 functions downstream of the KEAP1-PGAM5 signaling axis to mediate cell death in response to oxidative stress 34. AIFM1 also interacts with adenylate kinase 2 (AK2A) to regulate cellular energy metabolism by enhancing NADH oxidoreductase activity and creating metabolic enzyme hotspots within the intermembrane space 1. Clinically, AIFM1 mutations are associated with X-linked auditory neuropathy, particularly in non-infant patients, and the protein shows promise as a therapeutic target in cancer and inflammatory diseases 567.