Flavonoids in <i>Rosa roxburghii</i> Tratt Fermentation Broth Ameliorate Obesity via <scp>DNMT3a</scp> / <scp>SIRT1</scp> ‐Mediated Epigenetic Modulation

Obesity-related complications are often driven by chronic inflammation and oxidative stress, exacerbated by aberrant DNA methylation. Natural products with anti-inflammatory and antioxidant properties may offer therapeutic potential. This study investigated the potential molecular mechanisms underlying the effects of <i>Rosa roxburghii</i> Tratt fermentation broth (RRTFB) on obesity through targeted methylation, while also examining its primary active components and assessing its potential therapeutic value. Male SD rats were fed a high-fat diet (HFD) to induce obesity, with RRTFB administered as an intervention. Various methods, including reduced representation bisulfite sequencing analysis (RRBS), molecular docking, surface plasmon resonance (SPR), and other analytical methods were employed for the study. The results showed that, compared to the HFD-fed rats, the RRTFB intervention groups (HFH and HFL) exhibited a significant reduction in MDA, IL-6, TNF-α and DNMT3a levels, along with increased SOD, GSH-pX, and CAT activities in epididymal fat. RRBS revealed a significant number of differential methylation regions (DMRs) in genes related to fat metabolism, oxidative stress, and inflammation in HFD-fed rats and HFH. Protein interaction analysis and subsequent validation experiments identified SIRT1 as a key regulator mediating the efficacy of RRTFB: RRTFB reduced SIRT1 promoter methylation and enhanced its expression. In 3T3-L1 cells with Dnmt3a overexpression, SIRT1 levels were significantly reduced. ChIP-qPCR further confirmed an enhanced binding of Dnmt3a to the <i>SIRT1</i> promoter. Molecular docking and SPR confirmed that flavonoids, the active components of RRTFB, could directly bind to DNMT3a and modulate its activity. This study substantiates the potential of RRTFB as a phytochemo therapeutic strategy for combating obesity, highlighting its ability to mitigate obesity through DNMT3a/SIRT1-mediated epigenetic regulation, with flavonoids identified as the primary bioactive components.