Syringaresinol protects against diabetic nephropathy by inhibiting pyroptosis via NRF2-mediated antioxidant pathway

Diabetic nephropathy (DN) is one of the serious complications of diabetes that has limited treatment options. As a lytic inflammatory cell death, pyroptosis plays an important role in the pathogenesis of DN. Syringaresinol (SYR) possesses anti-inflammatory and antioxidant properties. However, the therapeutic effects and the underlying mechanism of SYR in DN remain unclear. Herein, we showed that SYR treatment ameliorated renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, and podocyte foot process effacement in streptozotocin (STZ)-induced diabetic mice. Mechanistically, SYR prevented the abundance of pyroptosis-related proteins such as NOD-like receptor family pyrin domain containing 3 (NLRP3), cysteinyl aspartate-specific proteinase 1 (Caspase-1), and gasdermin D (GSDMD), and the biosynthesis of inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18). In addition, SYR promoted the nuclear translocation of nuclear factor E2-related factor 2 (NRF2) and enhanced the downstream antioxidant enzymes heme oxygenase 1 (HO-1) and manganese superoxide dismutase (MnSOD), thereby effectively decreasing excess reactive oxygen species (ROS). Most importantly, knockout of NRF2 abolished SYR-mediated renoprotection and anti-pyroptotic activities in NRF2-KO diabetic mice. Collectively, SYR inhibited the NLRP3/Caspase-1/GSDMD pyroptosis pathway by upregulating NRF2 signaling in DN. These findings suggested that SYR may be promising a therapeutic option for DN.