MDL-800 protects against inflammatory and metabolic dysfunction: role of SIRT6 in the cross-regulation of NFκB, AMPK, and PPAR signaling in rats

Metabolic syndrome (MetSyn) is a complex, multifactorial disorder characterized by insulin resistance, dyslipidemia, hepatic steatosis, oxidative stress, and chronic inflammation, contributing substantially to the global burden of cardiometabolic diseases. Despite extensive research, effective pharmacological strategies that address the diverse and interconnected pathophysiological mechanisms of MetSyn are lacking. Sirtuin 6 (SIRT6), a NAD⁺-dependent epigenetic regulator, has emerged as a critical modulator of metabolic and inflammatory homeostasis. This study provides the first in vivo evidence that pharmacological activation of SIRT6 using MDL-800 confers robust systemic protection against MetSyn in a high-fat diet and streptozotocin-induced rat model. MDL-800 significantly improved survival rates, reduced weight gain and hepatomegaly, and ameliorated hepatic histopathological changes. It reversed dyslipidemia, hypertension, and hepatic dysfunction, restored antioxidant defenses, and enhanced glucose tolerance and insulin sensitivity. At the molecular level, MDL-800 restored hepatic SIRT6 activity, activated AMPK signaling, and upregulated the expression of PGC1α and PPARα, while suppressing NFκB activation, pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and the expression of PPARγ, sCD36, and β-hydroxybutyrate. Co-administration of the selective SIRT6 inhibitor OSS-128167 largely abrogated these beneficial effects, confirming the SIRT6-dependency of MDL-800's actions. Correlation and systems-level analyses further supported a central regulatory role of SIRT6 in modulating metabolic and inflammatory pathways associated with insulin sensitivity. Collectively, these findings position SIRT6 as a pivotal therapeutic target and establish MDL-800 as a hopeful candidate for the management of MetSyn and its related complications.