Sirtuin 6-driven ASC deacetylation confers hepatoprotection: A promising approach to inflammasome inhibition in...

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.