Nicotinamide riboside enhances chondrogenic differentiation of human adipose stem cells via inducing SIRT1-mediated deacetylation of SMAD7 and activation of TGF-β/SMAD2/3 pathway

Mesenchymal stem cells (MSCs) are widely regarded as a promising candidate for cartilage regeneration, and MSC-based therapies have demonstrated therapeutic potential in promoting cartilage repair. Nevertheless, the chondrogenic differentiation efficacy still requires further improvement. This study identified that Nicotinamide Riboside, a precursor of nicotinamide adenine dinucleotide (NAD⁺), significantly enhances chondrogenic differentiation efficiency of human adipose-derived stem cells (hADSCs), primary by activating the TGF-β/SMAD2/3 signaling pathway. Mechanistically, we demonstrated that NR upregulated the expression of SIRT1 and enhanced SIRT1 activity during the induction of chondrogenesis, thereby promoting the deacetylation and subsequent degradation of SMAD7. NR-mediated reduction of SMAD7 results in enhanced phosphorylation of SMAD2/3 and activation of the TGF-β/SMAD2/3 signaling pathway. SIRT1-mediated deacetylation of SMAD7 is a key factor in NR-enhanced chondrogenic differentiation, as disruption of the interaction between SIRT1 and SMAD7 significantly abolishes the promotive effect of NR on chondrogenesis. Collectively, our study demonstrates that NR enhanced chondrogenic differentiation of hADSCs by regulating SIRT1-mediated deacetylation of SMAD7 and activation of TGF-β/SMAD2/3 pathway. NR may therefore possess prospects as a promising supplement for MSC-based cartilage regeneration and repair therapies.