Piwil1, also known as HIWI, is a member of the PIWI subfamily of Argonaute proteins. It typically binds to PIWI-interacting RNAs (piRNAs) to form piRNA/PIWIL1 complexes. The primary function of PIWIL1/piRNAs is to silence transposable elements, protecting genome integrity in animal germlines. Additionally, it has been implicated in regulating gene expression at transcriptional or post-transcriptional levels [1,2].

In male infertility, ubiquitination-deficient mutations in human PIWIL1 were identified in infertile men, and these mutations were shown to cause male infertility in a mouse model, suggesting PIWIL1 is a male infertility-relevant gene [1].

In cancer, PIWIL1 is frequently overexpressed in various tumors compared to normal tissues. For example, in gastric cancer, knocking out the PIWIL1 gene (PIWIL1-KO) significantly reduces cell proliferation, migration, metastasis, and tumorigenesis, and its function is independent of piRNA, involving interaction with the UPF1-mediated nonsense-mediated mRNA decay (NMD) mechanism [4]. In glioblastoma, silencing Piwil1 in glioma stem-like cells leads to cell-cycle arrest, senescence, or apoptosis, and suppresses tumor growth in animal models [3]. In multiple myeloma, PIWIL1 promotes cell proliferation and chemoresistance, and its depletion could be a novel therapeutic target [5]. In papillary thyroid carcinoma, PIWIL1 promotes cell proliferation, cell cycle activity, invasion, and suppresses apoptosis, accelerating tumor growth by modulating EVA1A expression [7]. In hepatocellular carcinoma, PIWIL1 mediates the crosstalk of fatty acid metabolism and immune response, and its overexpression promotes tumor proliferation and growth [8]. In colorectal cancer, knockdown of PIWIL1 induces G2/M arrest, highlighting its role in cell cycle progression [6].

In conclusion, Piwil1 plays essential roles in both normal biological processes such as male germ cell development and in disease conditions like male infertility and multiple types of cancers. Gene knockout models, especially in mice, have been crucial in revealing these functions, providing insights into potential therapeutic targets for treating infertility and cancers associated with Piwil1 dysregulation.