Eftud2, also known as elongation factor Tu GTP binding domain containing 2, is a spliceosomal GTPase and an essential component of U5 small nuclear ribonucleoproteins (snRNPs) [3,4,5,6]. It is involved in spliceosome activation, playing a crucial role in the removal of introns from precursor mRNA, thus regulating embryonic development and innate immunity [6].

In gene knockout studies, specific ablation of Eftud2 in cerebellar Purkinje cells of mice led to severe ferroptosis, Purkinje cell degeneration, dyskinesia, and cerebellar atrophy, phenotypes similar to those in patients with mandibulofacial dysostosis with microcephaly (MFDM) syndrome [1]. Mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity to suppress Purkinje cell ferroptosis [1]. In microglia, Eftud2 deficiency caused by conditional knockout in a mouse line (CX3CR1-CreER; Eftud2f/f cKO) resulted in abnormal proliferation and promoted anti-inflammatory phenotype activation, potentially through the NF-κB signaling pathway [2]. In hepatocellular carcinoma (HCC), siRNA-mediated knockdown of Eftud2 in HCC cells suppressed cell viability, blocked cell cycle progression, facilitated apoptosis, and inhibited metastasis, while over-expression promoted proliferation and migration [3]. Eftud2 was also found essential for maintaining the survival of HCC cells, potentially via the activation of STAT3 [3].

In conclusion, Eftud2 is crucial for maintaining cell survival and function in various tissues. Mouse models with Eftud2 knockout or conditional knockout have revealed its role in neurodegenerative conditions like MFDM-related cerebellar atrophy and in cancer development, especially in hepatocellular carcinoma. These findings provide insights into potential therapeutic strategies for Eftud2-related disorders, such as targeting ferroptosis in MFDM-like phenotypes or inhibiting Eftud2 in HCC [1,3].