Pleiotropic regulatory mechanisms and targeted therapeutic prospects of Galectin-3 in aging-related diseases.

Aging is a major risk factor for numerous chronic diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), atherosclerosis (AS), type 2 diabetes mellitus (T2DM), osteoarthritis (OA) and age-related macular degeneration (AMD). Galectin-3 (Gal-3), a unique β-galactoside-binding lectin, has emerged as a critical mediator in the pathogenesis of AD and other age-related disorders by modulating key mechanisms such as inflammation, oxidative stress, and apoptosis. While emphasizing neurological disorders (AD, PD), this review also examines Gal-3's role in systemic age-related conditions (T2DM, AS, OA, AMD) that frequently co-occur with or influence neurodegeneration. This review summarizes current knowledge on the expression patterns, molecular mechanisms, and therapeutic potential of Gal-3 in aging-related diseases. Elevated Gal-3 levels have been detected in the brain tissue and cerebrospinal fluid of AD patients, where it contributes to multiple pathological processes, including microglia-driven neuroinflammation, Aβ plaque deposition, tau hyperphosphorylation, oxidative damage, and neuronal apoptosis. Furthermore, Gal-3 upregulation is observed across various age-related diseases and correlates with disease progression, underscoring its potential as a diagnostic biomarker and therapeutic target. Preclinical studies demonstrate that Gal-3-targeted interventions-including small-molecule inhibitors (e.g., TD-139), natural compounds (e.g., modified citrus pectin), and other pharmacological agents-exert neuroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects by binding to Gal-3 and modulating its activity in animal models, offering promising avenues for multi-disease treatment. However, the dual roles and complex regulatory networks of Gal-3 present challenges for clinical translation, requiring context-specific therapeutic approaches tailored to distinct disease mechanisms. Future research should focus on elucidating tissue-specific mechanisms and optimizing combination therapies to enable precise targeting of aging-related pathologies.