Vital pulp treatment (VPT) encompasses a range of biologically based procedures that aim to preserve the dental pulp, minimise intervention and improve long-term tooth survival. However, a lack of reliable, accurate diagnostic tests to assess the inflammatory status of the dental pulp coupled with use of outdated diagnostic nomenclature that does not support pulp preservation strategies, are two major limitations in effective implementation of VPT in clinical practice. This narrative review aims to discuss the limitations of the current diagnostic methods and the classification of pulp disease, while exploring emerging research on solutions designed to overcome these limitations. Contemporary evidence supports adoption of a pulp disease classification that best describes the disease as continuum, rather than dichotomous approach of reversible/irreversible pulpitis. The recent advances in understanding the pathophysiology of pulpitis at molecular level could be exploited for development of novel biomarker-based diagnostic chairside tests. Moving forward, a refinement of the nomenclatures describing pulpitis, together with integration of objective diagnostic technologies are crucial for improving the diagnostic accuracy and enabling more successful application of pulp preservation therapies and predictable treatment outcomes for patients.

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.