Spag6, or sperm-associated antigen 6, is a core axonemal component crucial for the formation of cilia and sperm flagella [2]. It also acts as a scaffolding protein in the center of the flagellar axoneme, influencing mammalian sperm flagella motility maturation and sperm structure maintenance [5]. In cells, it may be involved in multiple signaling pathways such as ROS/JNK MAPK, PI3K/AKT, and ERK, and is associated with various biological processes and diseases [1,3].

In acute myeloid leukemia (AML), SPAG6 over-expression promotes cell growth, reduces ROS levels, and decreases the pro-apoptotic effect of daunorubicin through the ROS/JNK MAPK axis in a GSTP1-dependent manner [1]. It also contributes to AML cell proliferation, migration, and cell-cycle progression by interacting with MYO1D, which regulates the EGFR family expression [3].

In myelodysplastic syndromes (MDS), SPAG6-knockdown enhances decitabine-induced apoptosis and demethylation of PTEN, and triggers autophagic cell death via the AMPK/mTOR/ULK1 signaling pathway [4,7].

In non-syndromic asthenoteratozoospermia with severe multiple morphological abnormalities of the sperm flagella (MMAF), homozygous SPAG6 variants can lead to this condition, as the level of SPAG6 protein is significantly decreased in spermatozoa [2].

In lung squamous cell carcinoma, DNMT3b-mediated SPAG6 promoter hypermethylation activates the JAK/STAT pathway to promote tumor progression [6].

In BCR::ABL1 negative myeloproliferative neoplasms (MPNs), up-regulated SPAG6 correlates with increased STAT1 and reduced sensitivity to interferon-α response [8].

In conclusion, Spag6 is essential for cilia and sperm flagella formation. Through gene-knockout or knockdown models in relevant disease studies, it has been shown to play significant roles in cancer (such as AML, MDS, and lung squamous cell carcinoma) and male infertility-related diseases. These findings help understand the underlying mechanisms of these diseases and may provide potential therapeutic targets.