PIWIL3 is a PIWI family protein essential for genome integrity in germ cells, primarily functioning in transposable element (TE) silencing through piRNA-mediated gene silencing 1. In oocytes, PIWIL3 localizes to mitochondria and forms a complex with TDRKH and PNLDC1, with approximately 50% of bound piRNAs mapping to transposable elements 2. PIWIL3 plays a critical non-redundant role during oogenesis and early embryogenesis; PIWIL3 deficiency in golden hamsters results in subfertility with delayed zygotic development, while PIWIL1 can partially compensate for TE silencing when PIWIL3 is absent 1. Beyond its germline function, PIWIL3 exhibits oncogenic activity in multiple cancers. It is significantly upregulated in lung cancer, melanoma, gastric cancer, and glioma tissues [PMID:35117181; 3; 4; 51]. PIWIL3 knockdown suppresses cancer cell proliferation, induces apoptosis, and inhibits metastasis in lung and gastric cancers, partially through JAK2/STAT3 signaling and epithelial-mesenchymal transition regulation [PMID:35117181; 60]. In pancreatic cancer, PIWIL3 contributes to maintaining cell homeostasis and undifferentiated phenotypes 7. These findings suggest PIWIL3 represents a potential therapeutic target in cancer, contrasting with its protective role in reproductive tissues.