Unraveling the Role of <i>Djstat5 </i>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 <i>Djstat5</i>, a STAT5 homolog in the planarian <i>Dugesia japonica</i>, and demonstrated that it is dynamically upregulated during the early regenerative phases. RNA interference (RNAi)-mediated knockdown of <i>Djstat5 </i>resulted in severe defects in tissue regeneration, including blastema hypoplasia, reduced mitotic activity, and diminished apoptosis. Transcriptomic analysis revealed that <i>Djstat5 </i>knockdown led to upregulation of <i>Djnlrc3</i>, a putative negative regulator of regeneration. Functional interaction between <i>Djstat5 </i>and <i>Djnlrc3</i> was further supported by double RNAi experiments, which showed that co-knockdown of <i>Djnlrc3 </i>significantly rescued the regeneration defects induced by <i>Djstat5 </i>loss. Together, our findings establish <i>Djstat5 </i>as an essential regulator of planarian regeneration and provide new insights into conserved STAT-mediated signaling pathways in adult stem cell-based tissue regeneration.