The Functions and Molecular Mechanisms of SIRT7 in Mediating Fate Determinations of Stem Cells and Its Translational Applications

Sirtuin 7 (SIRT7) is a nucleolus-enriched and NAD+-dependent deacylase that connects ribosomal DNA transcription, pre-rRNA processing, chromatin regulation, DNA-damage repair, mitochondrial proteostasis, and inflammatory restraint. These activities place SIRT7 at the interface between cellular homeostasis and stress adaptation. Nevertheless, current evidence does not support a single or universal direction of action of SIRT7 across stem cell systems. In hematopoietic stem cells (HSCs), SIRT7 is linked to the nuclear respiratory factor 1 (NRF1)-associated mitochondrial unfolded protein response (UPRmt) and preservation of quiescence under aging or regenerative stress. In human mesenchymal stem cells (MSCs), SIRT7 acts via heterochromatin stabilization and retrotransposon-associated inflammatory restraint. In addition, hair-follicle stem cells (HFSCs), neural stem cells (NSCs), dental pulp stem cells (DPSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been investigated in relation to SIRT7, with evidence varying across systems. Here we discuss the functions and molecular mechanisms of SIRT7 in controlling the fate determinations of various kinds of stem cells through deacetylation and desuccinylation, and we propose a stress-adaptation threshold framework as an interpretive model. Within this model, the output of SIRT7 may depend on basal stress level, regenerative demand, substrate availability, and temporal window. By separating direct catalytic events from downstream functional consequences and by grading evidence across stem cell systems, we propose that SIRT7 can be viewed as a context-dependent regulator of stem-cell state transitions rather than as a generic pro-regenerative, anti-aging, or pro-tumorigenic factor. Finally, we discuss potentially translational directions and priorities for future research, while noting that clinical applications remain to be explored further.