Unraveling the role of Djstat5 in planarian regeneration by modulating cell proliferation and apoptosis.

Signal transducer and activator of transcription (STAT) proteins function as key mediators of cytokine signaling and are critically involved in stem cell regulation, tissue regeneration, and immune responses in vertebrates. However, their roles in invertebrate regeneration, particularly in adult pluripotent stem cell systems like those of planarians, remain largely unexplored. In this study, we investigated the function of Djstat5, a STAT5 homolog in the planarian Dugesia japonica, and demonstrated that it is dynamically upregulated during the early regenerative phases. RNA interference (RNAi)-mediated knockdown of Djstat5 resulted in severe defects in tissue regeneration, including blastema hypoplasia, reduced mitotic activity, and diminished apoptosis. Transcriptomic analysis revealed that Djstat5 knockdown led to upregulation of Djnlrc3, a putative negative regulator of regeneration. Functional interaction between Djstat5 and Djnlrc3 was further supported by double RNAi experiments, which showed that co-knockdown of Djnlrc3 significantly rescued the regeneration defects induced by Djstat5 loss. Together, our findings establish Djstat5 as an essential regulator of planarian regeneration and provide new insights into conserved STAT-mediated signaling pathways in adult stem cell-based tissue regeneration.