Honokiol attenuates diabetic nephropathy by targeting SIRT3 to suppress mitochondrial ROS-induced pyroptosis.

BACKGROUND: Diabetic nephropathy (DN) persists as the leading cause of end-stage renal disease worldwide. Growing evidence indicates that mitochondrial dysfunction triggers NLRP3 inflammasome activation and subsequent pyroptosis, which play crucial roles in DN development. Honokiol (HKL), a natural compound with the ability to upregulate SIRT3 expression, shows promise in protecting mitochondrial function. This study investigates HKL's renoprotective effects in DN and explores its mechanism of action through the SIRT3-mediated regulation of mitochondrial ROS, NLRP3 inflammasome, and pyroptosis. MATERIALS AND METHODS: db/db diabetic mice and HK-2 cells subjected to hyperglycemic stimulation were used to assess the therapeutic effects of HKL. Renal function, pyroptosis, and mitochondrial homeostasis were assessed via biochemical assays, histopathological and immunohistochemical analyses, transmission electron microscopy, Western blotting, and immunofluorescence staining. SIRT3 overexpression and knockdown were performed to validate its regulatory role, while the mtROS scavenger MitoTEMPO was utilized to confirm the pivotal involvement of mtROS in the pyroptotic pathway. RESULTS: HKL treatment significantly ameliorated renal dysfunction and pathological damage in diabetic mice. Mechanistically, HKL upregulated SIRT3 expression, thereby improving mitochondrial function (maintaining structural integrity, stabilizing the membrane potential, and reducing mtROS accumulation), which in turn suppressed NLRP3 inflammasome activation and subsequent GSDMD-mediated pyroptosis. SIRT3 overexpression mimicked the protective effects of HKL, whereas SIRT3 knockdown attenuated its efficacy, confirming the essential role of SIRT3 in this process. Furthermore, mtROS scavenging by MitoTEMPO mitigated pyroptosis, reinforcing the dependence of the effects of HKL on the SIRT3-mtROS axis. CONCLUSION: By upregulating SIRT3 expression to maintain mitochondrial homeostasis and suppress mtROS-NLRP3-mediated pyroptosis, HKL emerges as a promising therapeutic strategy for DN.