Aifm2, also known as ferroptosis suppressor protein 1 (FSP1) and apoptosis-inducing factor mitochondria-associated 2, is a crucial NADH oxidase involved in the regulation of cytosolic NAD+ [2]. It participates in multiple biological pathways, such as being part of the non-mitochondrial CoQ antioxidant system that acts parallel to the GPX4 pathway to inhibit ferroptosis [4,5]. It is also associated with mitochondrial biogenesis, glycolysis, and apoptosis-related pathways, playing an important role in various biological processes and disease conditions. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In a severe acute pancreatitis (SAP) mouse model, knockout of ATF6, which is related to Aifm2 regulation, attenuated acinar injury, apoptosis, and ER disorder. Aifm2, as a downstream regulatory partner of ATF6, could re-establish the pathological disorder in SAP tissues in the absence of ATF6, indicating its role in acinar apoptosis during SAP progression [1]. In hepatocellular carcinoma (HCC), knockdown of Aifm2 significantly impaired HCC metastasis, while forced expression enhanced it. Mechanistically, Aifm2 promoted metastasis by enhancing mitochondrial biogenesis through activation of SIRT1/PGC-1α signaling [2]. In skeletal muscle, muscle-specific Aifm2 depletion decreased exercise capacity and glucose utilization in mice, while overexpression increased exercise capacity with increased glucose utilization, showing its role in glucose utilization during high-intensity aerobic exercise [3].

In conclusion, Aifm2 is essential in processes like ferroptosis inhibition, cancer cell metastasis, and glucose utilization. The KO/CKO mouse models have significantly contributed to understanding its role in diseases such as severe acute pancreatitis and hepatocellular carcinoma, providing insights into potential therapeutic targets for these diseases.