Guardians of the germline, drivers of malignancy: piRNA-associated proteins as shared epigenetic regulators of infertility and cancer.

PIWI-interacting RNAs (piRNAs) and their associated proteins constitute an important regulatory system involved in genome stability, transposable-element repression, germ-cell development, and epigenetic regulation. Increasing evidence indicates that disruption of piRNA-associated proteins contributes to reproductive disorders and tumorigenesis through alterations in DNA methylation, histone modifications, RNA stability, and transposable-element activity. This review summarizes current evidence on the epigenetic functions of piRNA-associated proteins in infertility and cancer, with particular emphasis on TDRKH, PNLDC1, TDRD9, HENMT1, MORC1, MORC3, and other components of the piRNA pathway. Studies in mouse and zebrafish models demonstrate that defects in these proteins can impair piRNA biogenesis or stability, disrupt transposon silencing, alter germ-cell development, and result in male or female infertility. In human and cancer models, dysregulation of piRNA pathway components has been associated with ovarian, cervical, esophageal, breast, leukemia, and prostate cancers, with evidence implicating DNA and histone methylation as well as RNA modifications such as m6A and m5C. Collectively, these findings suggest that piRNA-associated proteins can act as important epigenetic regulators linking small-RNA-mediated mechanisms to genome integrity, reproductive function, and malignant transformation. Further characterization of these pathways may improve understanding of disease mechanisms and support the identification of potential diagnostic and therapeutic targets.