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Background: Obesity leads to massive death worldwide by initiatingnumerous illnesses like NASH, liver disease, and cardiovascular diseases. Developing new therapeutics against obesity is an emergency need. Targeting mitochondrialuncoupling protein 1 (UCP1) will provide new therapeutic strategies for the drug discovery research against obesity and obesity related disorders.
Methods:We screenedUCP1 up-regulators from epigenetic drug libraries  by using a previously developed Ucp1-A-GFP cellular GFP screening platform, ATP production, and mitochondrial DNA quantification.
Results:We discovered that the histone methyltransferase G9a inhibitor UNC0631 has a considerable effect on the expression of UCP1 in adipocytes when used in vitro. Here, we discovered that UNC0631 is crucial for controlling mitochondrial activity and anti-obesity. The UNC0631-treated fat cells have higher UCP1 expression at the cellular level.Taken together, in our studies, we have established an efficient in vitro cell experiment system to study the metabolic regulation of UCP1. Enhanced mitochondrial DNA, ATP synthesis, and cell survival showed that UNC0631 had a benign impact on the HEK293T cell line. As a result, UNC0631 reveal a promising therapeutic option for the treatment of diseases associated with obesity and metabolic disorders.
Conclusion:In this study, we make a list of potent drug candidatesfrom epigenetic drug libraries that can upregulate mitochondrial UCP1 gene expression and promote thermogenesis. UNC0631 improves mitochondrial function would be an effective drug candidate to treat metabolic diseases and obesity-related diseases. Further investigation will require both the human and animal models to reveal new insight into the mechanism against obesity, metabolic diseases,or mitochondrial dysfunction-related diseases.


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