The present systematic review aimed to combine the evidence on rodent models on molecular regulators of root dentinogenesis across the temporal phases and spatial zones, and evaluate the translation of this map for human dental development and regenerative therapies. A PRISMA 2020‑guided systematic review of experimental studies through the major electronic databases was performed. Data on models, molecules, techniques, spatiotemporal expression and the functional outcomes were extracted. The ARRIVE guidelines and SYRCLE's risk of bias tool were used to assess the risk of bias in animal studies. The evidence form rodent studies supports an organized network that begins with initiation at the cervical loop that requires the downregulation of mesenchymal fibroblast growth factor (FGF)10 and the activation of epithelial Sonic hedgehog (SHH) and mesenchymal bone morphogenetic protein (BMP)2/4. During elongation, the cervical zone exhibits high nuclear factor IC (NFIC), BMP/TGF‑β and dentin sialoprotein (DSPP) activity associated with differentiation, whereas the apical zone maintains proliferation through SHH, FGF2 and Wnt signaling. Maturation involves the upregulation of dentin sialophosphoprotein (DSPP) and dentin matrix protein 1 (DMP1), followed by Hertwig's epithelial root sheath (HERS) disintegration. The signaling crosstalk indicates that NFIC modulates Hh through Hhip, BMP/TGF‑β inhibits Wnt to prevent ossification and RUNX2 activates the Wnt inhibitor, Notum. The rodent‑derived spatiotemporal framework reveals evidence of conservation for selected molecular pathways in human genetic and cellular studies, while the extent to which the complete spatial and temporal organization is conserved in human root development remains incompletely defined. The synthesis therefore provides a conceptual basis for further mechanistic and preclinical investigation of biomimetic regenerative strategies.
