The piRNA–PIWI axis and m⁶A RNA methylation in cancer: Emerging intersections

Epigenetic and epitranscriptomic mechanisms play important roles in cancer development and progression. PiRNAs and N6-methyladenosine (m⁶A) RNA modification are increasingly recognized as important regulators of gene expression, cellular plasticity, tumor progression, and therapeutic resistance. This review summarizes current evidence on the piRNA–PIWI axis and m⁶A regulation in cancer, with particular emphasis on their emerging functional interplay. We discuss the mechanisms underlying piRNA biogenesis and PIWI protein function, as well as the major regulators of m⁶A deposition, recognition, and removal. Importantly, current evidence predominantly supports a piRNA-to-m⁶A regulatory mechanism, in which specific piRNAs modulate components of the m⁶A machinery, including METTL3, METTL14, WTAP, and YTHDF2. In contrast, evidence for reciprocal regulation of piRNAs by m⁶A remains limited and requires further investigation. We also discuss the potential involvement of this regulatory interplay in tumor growth, metastasis, cancer stemness, and therapeutic resistance, as well as its possible diagnostic and therapeutic implications. Overall, the piRNA–m⁶A connection represents an emerging area of cancer biology, but further mechanistic, translational, and clinical studies are required to establish its therapeutic relevance.