The PWWP domain is a conserved motif unique to eukaryotes, playing a critical role in various cellular processes. Proteins containing the PWWP domain are typically found in chromatin, where they bind to DNA and histones in nucleosomes, facilitating chromatin-associated functions. Among these proteins, PWWP-domain containing proteins 2A and 2B (PWWP2A and PWWP2B), identified during the H2A interactome analysis, are DNA methyltransferase-related proteins, that are structurally disordered, except for their PWWP domain. While their precise functions remain to be fully elucidated, PWWP2A and PWWP2B have been implicated in essential processes such as embryonic development, mitotic regulation, adipose thermogenesis, transcriptional control, and DNA damage response. Their involvement in disease pathology is an emerging area of research, with PWWP2B downregulation linked to recurrent gastric cancer, promoting cell proliferation and migration. Literature reveals that the circular RNA, cPWWP2A sequesters miR-203, miR-223, and miR-27, to modulate TGF-β signalling by inhibiting key regulators like SMAD3 and SP3. Additionally, PWWP2A/B proteins may interact with P4HA3, a regulator of the TGF-β/SMAD signalling pathway that influences tumour invasiveness, though the precise nature of this interaction is not yet fully understood. The PWWP2-miRNA-TGF-β axis, particularly the PWWP2-P4HA3 association, provides valuable insights into therapeutic strategies, especially under adverse conditions where this pathway is differentially regulated. Overall, given their essential roles in fundamental cellular processes and their involvement in disease mechanisms, PWWP2A and PWWP2B proteins could be ideal targets for therapeutic intervention. Thus, these proteins occupy a prominent position in the human proteome and epigenetic landscape. © 2025 Elsevier B.V., All rights reserved.