Guardians of the genome, allies of resistance: Unraveling the role of piRNAs and PIWI proteins in chemotherapy evasion

The PIWI-interacting RNA (piRNA) pathway, historically recognized for its essential role in germline transposon silencing, has recently emerged as a critical regulator of chemotherapy response in human malignancies. This review synthesizes current evidence establishing the piRNA-PIWI protein axis as a pivotal determinant of chemoresistance across diverse cancer types. Distinct family members exert opposing effects on drug sensitivity. Pro-resistance piRNAs including piR-137463, piR-1919609, piR-4447944, and piR-17560 drive chemoresistance through convergent mechanisms involving stemness maintenance, evasion of apoptosis, activation of pro-survival signaling cascades, and metabolic reprogramming. Conversely, chemosensitizing piRNAs such as piR-43452, piR-36712, and piR-39980 enhance therapeutic efficacy by targeting metabolic enzymes, modulating DNA repair, or restoring apoptotic pathways. PIWIL1 and PIWIL2 proteins emerge as central mediators of chemoresistance, functioning through mechanisms extending beyond canonical piRNA biogenesis, including cancer stem cell maintenance, autophagy/mitophagy-dependent survival, epigenetic reprogramming, and DNA damage repair modulation. The preferential expression of PIWI proteins in malignant tissues with minimal somatic expression offers a favorable therapeutic window for targeted interventions. Clinically, piRNA/PIWI expression levels consistently correlate with tumor stage, patient survival, and treatment response, supporting their utility as prognostic and predictive biomarkers, with piR-1077 in gastric juice representing a non-invasive diagnostic opportunity. Despite these promising developments, challenges remain including context-specific functional duality, potential off-target effects, and the need for efficient delivery systems. This review highlights the piRNA-PIWI network as both a sophisticated regulatory system influencing chemotherapy response and a promising therapeutic target, while identifying critical knowledge gaps that warrant further investigation, including comprehensive interactome mapping, tumor microenvironment interactions, and validation in prospective clinical cohorts.