ATG9A, one of the two mammalian homologs of yeast Atg9, is ubiquitously expressed and is an essential core member of the autophagy machinery [3]. It functions as a lipid scramblase allowing lipid equilibration across a membrane bilayer, crucial for autophagosome formation. Autophagy, in which ATG9A is involved, is a highly conserved pathway for maintaining cellular homeostasis, degrading damaged organelles, and surviving pathological conditions [5]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its function.

In ATG9A-related functional studies, ablation of ATG9A in macrophages causes aberrant TLR4 endosomal trafficking and decreases IRF-3 phosphorylation in LPS-stimulated macrophages, suggesting its role in regulating oxidative stress-induced autophagy through TRAF6-mediated K48/K63-linked ubiquitination [1]. Also, ATG9A and FIP200 promote the degradation of cytotoxic complex IIa via an LC3-independent lysosomal targeting pathway, counteracting TNF receptor 1-mediated embryonic lethality and inflammatory skin disease in mouse models [2]. In asthma, inhibiting the ULK1/Atg9a/Rab9 signaling pathways can reduce NLRP3-mediated pulmonary epithelial inflammation, Golgi apparatus fragmentation, and mitochondrial oxidative stress [4].

In conclusion, ATG9A is crucial for autophagosome formation and plays significant roles in regulating oxidative stress-induced autophagy, preventing TNF cytotoxicity, and in the context of asthma-related inflammation and cellular stress. The use of KO/CKO mouse models has provided valuable insights into its functions in these specific disease-related biological processes.