Htra2, also known as Omi, is a mitochondrial serine protease and an integral member of the HtrA family of serine proteases conserved from prokaryotes to humans [2]. It plays a crucial role in mitochondrial quality control, participating in the degradation of mis-accumulated proteins in the mitochondrial unfolded protein response (UPRmt) through its enzymatic activity, and regulating mitochondrial dynamics-related protein interactions to maintain mitochondrial morphology [1]. Htra2 is also involved in multiple cellular networks, with functions in apoptosis, autophagy, and inflammatory response regulation, making it important in maintaining cellular homeostasis [2,3].

In a collagen-induced arthritis mouse model, HtrA2 deficiency ameliorates pro-inflammatory cytokine expression in macrophages by controlling TRAF2 stabilization, indicating its role in macrophage polarization-related systemic chronic inflammation [1]. In aging germinal vesicle oocytes, insufficient HtrA2 causes meiotic defects, such as failure to complete meiosis, spindle/chromosome disorganization, and aneuploidy, suggesting its importance in female reproduction [4]. In microglia, HtrA2 knockdown promotes α -Synuclein-mediated mitochondrial reactive oxygen species production, activating microglial cells, which is relevant to the pathogenesis of Parkinson's disease [5].

In conclusion, Htra2 is essential for mitochondrial function, cell death regulation, and immune response modulation. Gene knockout (KO) or conditional knockout (CKO) mouse models have revealed its roles in diseases like systemic chronic inflammation, female reproductive failure, and potentially Parkinson's disease, providing valuable insights into disease mechanisms and potential therapeutic targets.