Molecular Mechanisms and Therapeutic Potential of Mulberry Fruit Extract in High-Fat Diet-Induced Male Reproductive Dysfunction: A Comprehensive Review

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High-fat diet (HFD)-induced obesity represents a significant challenge to male reproductive health, affecting approximately 13% of the global adult population. This comprehensive review synthesizes current evidence regarding mulberry (Morus alba L.) fruit extract’s therapeutic potential for HFD-induced male reproductive dysfunction. Through comprehensive analysis of the peer-reviewed literature from multiple databases (PubMed, Web of Science, Scopus, and Google Scholar; 2005–2024), we evaluated mulberry extract’s effects on testicular morphology, spermatogenesis, sperm parameters, and the underlying molecular mechanisms. Mechanistic studies reveal that standardized mulberry extract mediates protective effects through multiple pathways: enhanced antioxidant enzyme activities (SOD: +45%, Catalase: +38%, GPx: +35%), reduced inflammatory markers (TNF-α: −64%, IL-6: −58%), and modulated NF-κB signaling (−42.3%). These effects are facilitated by mulberry’s rich phytochemical profile, particularly anthocyanins (2.92–5.35 mg/g dry weight) and polyphenols (4.23–6.38 mg/g). The extract demonstrates particular efficacy in preserving seminiferous tubule integrity and maintaining blood-testis barrier function, with treated groups maintaining up to 85% of normal tubular architecture compared to HFD controls. Key molecular mechanisms include AMPK/SIRT1 pathway activation (2.3-fold increase), enhanced mitochondrial function (67% increase in mtDNA copy number), and epigenetic regulation of metabolic pathways. Temporal analysis indicates optimal therapeutic effects after 28 days of treatment, with initial improvements observable within 14 days. While current evidence is promising, limitations include predominant reliance on rodent models and lack of standardized extraction protocols. Future research priorities include well-designed human clinical trials, standardization of preparation methods, and investigation of potential synergistic effects with other therapeutic agents. This comprehensive review indicates that mulberry extract is a promising therapeutic candidate for obesity-related male infertility, warranting further clinical investigation.