piRNA/PIWI pathways and epigenetic crosstalk in human diseases: Molecular insights into HIV-1 infection and drugs of abuse.

P-element-induced wimpy (PIWI)-interacting RNAs (piRNAs) and PIWI proteins have long been studied in insects and germline cells for their roles in regulating transposable elements (TEs). However, emerging evidence suggests that piRNAs and PIWI proteins also play crucial roles in human diseases beyond gametocyte protection, and these molecules are implicated in the onset and progression of various human diseases, particularly those arising in somatic cells. Notably, piRNAs and PIWI proteins are increasingly recognized for their involvement in cancers, cardiovascular diseases, neurodegenerative disorders, and viral infections, including HIV. This review first provides an overview of piRNAs/PIWIs and their interactions with TEs and primary targets. We then explore the molecular mechanisms and signaling pathways through which piRNAs and PIWIs modulate human disease processes, focusing on neurodegeneration, cancers, and HIV. Special attention is given to the role of piRNA/PIWI complexes in regulating gene transcription, translation, and post-translational modifications in the context of disease. Additionally, we address emerging research into the role of piRNAs/PIWIs in HIV- and drug abuse or substance abuse-associated neurodegenerative diseases, highlighting existing knowledge gaps. Finally, we discuss future research directions to understand better the functions of piRNAs/PIWI proteins in human health and disease.