Polydatin Could Ameliorate Type 2 Diabetes Mellitus-Induced Nonalcoholic Fatty Liver by Suppressing Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells/Nucleotide-Binding Domain, Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Contai

Objective: Nonalcoholic fatty liver disease (NAFLD) has a global prevalence of 25% and is the main complication of type 2 diabetes mellitus (T2DM) related liver disease, bringing a serious global burden. Polydatin (PD), a compound from the traditional medical herb, was commonly used to protect and treat liver-related disorders. However, its potential mechanism remains unclear. Materials and Methods: The objective of our research was to explore the hepatoprotective properties and the mechanisms involved with PD in the context of NAFLD induced by T2DM. Both in vivo and in vitro models of T2DM-induced NAFLD and PD intervention were developed using db/db mice and HepG2 cell lines. Histopathological staining, immunofluorescence, Western blotting, enzyme-linked immunosorbent assay, and flow cytometry were conducted to identify the therapeutic effects of PD in treating T2DM-induced NAFLD. Results: The results revealed that PD alleviated inflammatory cytokine levels and markedly reduced T2DM-induced histological alterations of livers. In addition, PD restored alanine aminotransferase, aspartate aminotransferase, and lipid metabolism in db/db mice. Furthermore, PD could ameliorate palmitic acid-induced inflammation and pyroptosis by regulating the expressions of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), p-NF-κB, IKK, p-IKK, nucleotide-binding domain, leucine-rich repeat-containing receptor, pyrin domain-containing 3 (NLRP3), ASC, caspase-1, and apoptosis-related proteins. The related pathway inhibitors (Bay 11-7082 and CY-09) and molecular docking analysis further confirmed the effectiveness of PD in treating liver inflammation. Conclusions: Our results indicated that PD could serve as a promising candidate for therapy in addressing NAFLD induced by T2DM, potentially through the inhibition of the NF-κB/NLRP3 inflammasome axis activation within the liver.