Glycation of Salivary Aldehyde Dehydrogenase: Emerging Molecular Mechanisms and Clinical Implications in Oral Disease

Salivary aldehyde dehydrogenases (ALDHs), particularly ALDH3A1 and ALDH1A1, serve as frontline enzymatic defenses in the oral cavity, detoxifying reactive aldehydes generated through metabolic activity, microbial fermentation, and environmental exposures. These enzymes are essential for maintaining redox homeostasis, mucosal integrity, and immune modulation. However, under chronic metabolic stress, such as in diabetes, oral inflammation, and cancer, salivary ALDHs become vulnerable to non-enzymatic glycation by reactive carbonyl species like methylglyoxal. This modification impairs cofactor binding, catalytic activity, and structural stability, thereby compromising detoxification capacity at a time of heightened aldehyde burden. This review provides the first insights into ALDH glycation and particularly that of salivary ALDH, examining its structural mechanisms, disease-specific consequences, and emerging protective strategies. Special focus is given to natural compounds, including curcumin, thymoquinone, resveratrol, carnosine, and EGCG, that prevent glycation or restore ALDH function via carbonyl scavenging, antioxidant activation, and NAD⁺/SIRT1 pathway modulation. We also highlight critical research gaps, such as the absence of site-specific glycation maps, lack of salivary gland-based models, and limited availability of ALDH3A1-specific activators. Importantly, we propose that the glycation status of salivary ALDHs may serve as a non-invasive biomarker of oxidative stress and therapeutic response in metabolic and inflammatory disorders. By bridging biochemical insights with translational potential, this review establishes ALDH glycation as a mechanistic and clinically actionable axis in oral and systemic health.