A novel HSF1 activator ameliorates non-alcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation

Background and Purpose: Non-alcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD) and no pharmacological treatment as yet been approved. Identification of novel therapeutic targets and their agents is critical to overcome the current inadequacy of drug treatment for NASH. Experimental Approach: The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were investigated by chromatin-immunoprecipitation sequencing. The effects and mechanisms of SYSU-3d in alleviating NASH were examined in relevant cell models and mouse models (the Ob/Ob mice, high-fat and high-cholesterol diet and the methionine-choline deficient diet-fed mice). The actions of SYSU-3d in vivo were evaluated. Key Results: HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly identified activator SYSU-3d effectively inhibited all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of PPAR gamma coactivator-1 alpha (PGC-1 alpha) to induce mitochondria! biogenesis. Thus, increasing mitochondrial adaptive oxidation and inhibiting oxidative stress. The deletion of HSF1 and PGC-1 alpha or recovery of HSF1 in HSF1-deficiency cells showed the HSF1/PGC-1 alpha pathway was mainly responsible for the anti-NASH effects of SYSU-3d independent of AMP-activated protein kinase (AMPK). Conclusion and Implications: Activation of HSF1 is a practical therapeutic approach for NASH treatment via the HSF1/PGC-1 alpha/mitochondrial pathway and SYSU-3d can be considered as a potential candidate for the treatment of NASH.

Automated summary

This study found that activation of heat shock factor 1 (HSF1) can alleviate non-alcoholic steatohepatitis (NASH) through the HSF1/PPAR gamma coactivator-1 alpha (PGC-1 alpha)/mitochondrial pathway, and SYSU-3d can be considered as a potential candidate for NASH treatment.