MDL-811

Nonalcoholic steatohepatitis (NASH), a progressive subtype of metabolic-associated steatotic liver disease (MASLD), is characterized by hepatocellular injury, inflammation, oxidative stress, and fibrosis. Sirtuin 6 (SIRT6), a deacetylase, plays a crucial role in regulating hepatic metabolic and inflammatory pathways. This work assessed the therapeutic potential and underlying mechanism of MDL811, a selective SIRT6 activator, in a rat model of NASH induced by diethylnitrosamine, high-fat diet, and thioacetamide. Rats were treated with MDL811 alone or in combination with the SIRT6 inhibitor SIRT6-IN-1. MDL811 significantly improved liver function markers, lipid profile, and antioxidant enzyme activity, while reducing hepatic steatosis, inflammation, and fibrosis. Mechanistically, MDL811 enhanced hepatic SIRT6 activity and exerted anti-inflammatory effects by reducing acetylation of the inflammasome adaptor ASC, suppressing NLRP3 inflammasome activation, and decreasing nuclear NFκB p65 activity and downstream cytokine expression. In parallel, MDL811 attenuated fibrosis by inhibiting SMAD2/3 phosphorylation and downregulating fibrotic markers such as α-SMA, TGF-β1, and TIMP-1, while restoring PPARα expression. Co-treatment with SIRT6-IN-1 abolished the beneficial effects of MDL811 on inflammation, fibrosis, oxidative stress, and lipid metabolism, confirming the central role of SIRT6 activation. Notably, SIRT6-IN-1 alone reduced hepatic SIRT6 activity in control animals without inducing significant pathology, but selectively worsened inflammatory and fibrogenic pathways in the NASH context. These findings show that MDL811 protects against NASH through SIRT6-dependent inhibition of inflammasome signaling, with ASC deacetylation identified as a key mechanism. Modulating the SIRT6-ASC axis may therefore represent a promising strategy for managing inflammation-driven diseases such as NASH.

Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke, but how to control the overactive neuroinflammation is still a long-standing challenge. Here, we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia, which were abolished by silencing SIRT6. RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811 stimulation and is required for the anti-inflammatory effects of MDL-811. We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation. Moreover, our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS, but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery. Importantly, MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients, underlying an interesting translational perspective. Taken together, MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation.