Proteolytic enzymes in dentin erosion: roles of matrix metalloproteinases and cathepsins and the effectiveness of synthetic and natural inhibitors—a systematic review

OBJECTIVES: To evaluate the role of matrix metalloproteinases (MMPs) and cathepsins in dentin erosion and assess the efficacy of synthetic and natural inhibitors in preventing collagen matrix degradation and preserving dentin integrity. METHODS: A systematic literature search was conducted and updated in January 2025 across PubMed, Scopus, and Web of Science, targeting studies that investigated the role of matrix metalloproteinases (MMPs) and/or cysteine cathepsins in dentin erosion or erosion-abrasion models. In vitro, in situ, and in vivo experimental studies evaluating the effects of synthetic and natural protease inhibitors were included. Study selection, data extraction, and risk of bias assessment were performed following PRISMA 2020 guidelines. RESULTS: A total of 22 studies met the inclusion criteria, comprising predominantly in vitro designs, alongside in situ and combined experimental models. Across studies, MMP-2, MMP-8, and MMP-9, together with cathepsin K, were consistently identified as key enzymes involved in collagen degradation following acidic challenges. Erosive protocols varied in pH, exposure time, and cycling frequency, but uniformly promoted demineralization and enzymatic activation. Synthetic inhibitors (e.g., ferrous sulfate, stannous fluoride) and natural compounds (e.g., green tea catechins, theaflavins) demonstrated significant reductions in enzymatic activity and dentin loss. Importantly, studies assessing combined inhibition of MMPs and cathepsins reported the greatest protective effects, supporting a multimodal strategy to limit erosive dentin degradation. CONCLUSIONS: Acidic challenges promote the activation of matrix metalloproteinases and cysteine cathepsins, thereby accelerating dentin erosion through progressive collagen degradation. Both synthetic and natural inhibitors were shown to attenuate proteolytic activity and reduce dentin loss under experimental conditions. Notably, strategies targeting multiple enzymatic pathways consistently demonstrated greater protective effects than single-agent approaches. Nevertheless, the predominance of in vitro and in situ evidence highlights the need for well-designed clinical studies to confirm the long-term efficacy and translational relevance of these interventions. CLINICAL SIGNIFICANCE: The incorporation of MMP and cathepsin inhibitors into preventive and therapeutic oral care strategies represents a promising adjunct for enhancing dentin resistance to erosive challenges. However, clinical implementation requires standardized experimental protocols, clearer dose-response characterization, and validation in long-term clinical settings. Advancing dual-targeted inhibitory approaches may contribute to more effective and durable dentin preservation in patients at risk of erosive tooth wear.