Targeting Hypoxic Pathways for Dental Pulp Regeneration

Hypoxia is a critical feature of the dental pulp microenvironment, influencing stem cell behavior and tissue regeneration. Hypoxia-inducible factor 1-alpha (HIF-1α), the master transcription factor governing cellular adaptation to hypoxic stress, plays a pivotal role in coordinating biological processes essential for pulp regeneration. Accumulating evidence suggests that hypoxia and HIF-1α activation enhance the proliferation and odontogenic differentiation of dental pulp stem cells (DPSCs) by inducing autophagy and metabolic reprogramming. Moreover, hypoxia and HIF-1α-related signaling modulate DPSC secretome, including extracellular vesicle composition and para-/autocrine signaling, thereby supporting neovascularization and immunomodulation. Precise regulation of HIF-1α expression and activity offers promising approaches to facilitate pulp tissue regeneration. Strategies to modulate HIF-1α include transcriptional and translational control of HIF-1α expression, inhibition of prolyl hydroxylase domain enzymes (PHDs) to stabilize HIF-1α, and prevention of its ubiquitin-proteasome-mediated degradation. Accordingly, therapeutic interventions such as hypoxic preconditioning, the use of hypoxia-mimetic agents (e.g., deferoxamine, dimethyloxalylglycine), and gene modulation targeting PHD expression have been explored to leverage hypoxia-induced regenerative mechanisms. Furthermore, controlled oxygen-releasing biomaterials have recently emerged as a complementary approach to mitigate hypoxia within the pulp microenvironment, enhancing regenerative outcomes. Collectively, these approaches highlight the potential of targeting hypoxia and HIF-1α signaling to inform the development of novel pharmacological, gene-based, and biomaterial-based strategies for advancing regenerative endodontic therapies.