Obesogenic diets coupled with type-2 diabetes accelerate hepatic fat buildup, oxidative stress, and chronic inflammation, driving progression to non-alcoholic steatohepatitis (NASH). Sirtuin 2 (SIRT2) has been implicated in both metabolic and inflammatory regulation, but its role in NASH remains unclear. Here, we investigated the effects of pharmacological SIRT2 activation with nicotinamide riboside (NR) versus inhibition with AGK2 in a diabetic dietary (STZ-HFD) rat model of NASH. NR treatment improved fasting glucose, insulin resistance, and oral glucose tolerance, and reduced steatosis, dyslipidemia, and transaminase elevations. Histology confirmed decreased inflammation, oxidative stress, and fibrosis. Mechanistically, NR promoted SIRT2-mediated deacetylation of NLRP3, LKB1, and FOXO3a, suppressing inflammasome activation (caspase-1 cleavage, IL-1β, IL-18, GSDMDN) and restoring AMPK signaling with downstream ACC inhibition, PGC-1α-Nrf2 activation, and Gadd45a induction. These effects improved lipid oxidation, antioxidant defenses, and redox balance, thereby attenuating both NF-κB-dependent "signal 1" priming and ROS-driven "signal 2" activation of the NLRP3 inflammasome. Pharmacologic SIRT2 inhibition with AGK2 attenuated NR-mediated improvements across metabolic and hepatic endpoints, confirming SIRT2's contribution but suggesting additional NAD-dependent mechanisms. Our study clarifies a long-standing controversy around whether SIRT2 should be activated or inhibited in metabolic liver disease, providing direct pharmacologic evidence that SIRT2 activation is protective. Collectively, these findings identify SIRT2 as an integrative regulator of metabolism and inflammation in NASH, with NLRP3 deacetylation and AMPK-ACC/PGC-1α-Nrf2 restoration as pivotal therapeutic nodes. As no selective activators of SIRT2 are currently available, our results highlight the urgent need to develop such agents for metabolic liver disease. +
