Ciao2a, also known as FAM96A, is an evolutionarily conserved protein involved in cytosolic iron-sulfur (Fe-S) cluster assembly, regulating cellular iron (Fe) homeostasis [1,2,3,4,5,6,7]. It is associated with pathways like mTOR signaling, interferon/STAT1 signaling, TGFβ1 signaling, and immunometabolism, and is crucial for maintaining organismal energy balance, adipose tissue homeostasis, host control of Toxoplasma gondii infection, and intestinal homeostasis [1,2,7]. Genetic models, such as knockout mice, have been essential in studying its functions.

In mice with global or adipocyte-selective FAM96A deficiency, intracellular Fe homeostasis was disrupted in adipocytes, leading to adipocyte hypertrophy, reduced organismal energy expenditure, and increased fat mass accumulation due to enhanced mTOR signaling. Brown adipocytes also showed mitochondrial defects [1]. Myeloid cell-specific deletion of Fam96a in mice exacerbated acute and chronic toxoplasmosis, as it disrupted macrophage polarization and iron homeostasis [2]. FAM96A-knockout mice resisted sepsis, with FAM96A-deficient macrophages promoting M2 macrophage transformation [4]. Fam96a -/- mice had increased susceptibility to DSS-induced colitis due to gut microbial dysbiosis [7].

In conclusion, Ciao2a (FAM96A) is a key regulator in multiple biological processes. Gene knockout mouse models have revealed its significance in diseases related to metabolism (such as obesity-related disorders), infectious diseases (like toxoplasmosis), sepsis, and intestinal inflammation (colitis), providing insights into disease mechanisms and potential therapeutic targets.