Curcumin Analog J7 Attenuates Liver Fibrosis and Metabolic Dysregulation in a Rat Model of Type 2 Diabetes via Modulation of TGF-β/Smad and NF-κB/BCL-2/BAX Pathways

Jun Ma,1 Wei Chen,2 Deep K Vaishnani,3 Congying Wang,2 Shuman Xue,2 Qiuqin Yang,4 Yuheng Tong,4 Ningjia Lei,5 Zhichao Zhao,6 Furong Ying7 1Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China; 2Renji College, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 3School of International Studies, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 4School of Clinical Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 5Pharmacy College, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China; 6Department of Critical Care Medicine, Yuyao People’s Hospital, Yuyao, Zhejiang, 315400, People’s Republic of China; 7Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of ChinaCorrespondence: Furong Ying, Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People’s Republic of China, Email [email protected]: To evaluate the therapeutic potential of the curcumin analog J7 in protecting the liver and regulating glucose and lipid metabolism in rats with type 2 diabetes.Methods: Bioinformatics methods were used to identify signaling pathways linked to diabetic liver disease. Diabetic rats were treated with curcumin, low-dose J7, or high-dose J7, and liver function and fibrosis were assessed through biochemical analyses, histopathology, immunohistochemistry, and ELISA.Results: J7 administration significantly improved lisver function, reduced fibrosis, and regulated metabolic profiles in diabetic rats. J7 downregulated TGF-β 1, NF-κB p65, and BAX, while upregulating BCL-2, showing superior effects to traditional curcumin in reducing TGF-β 1 and inhibiting α-SMA expression.Conclusion: J7 demonstrates potential as a therapeutic agent for managing liver complications in type 2 diabetes, effectively attenuating liver fibrosis and regulating metabolism through the modulation of key signaling pathways and proteins.Plain Language Summary: Diabetes is a common condition that can cause serious problems in the liver, such as damage and scarring (fibrosis). These problems are linked to how the body handles sugar and fat. Right now, there are not many effective treatments for diabetes-related liver issues. Our study looked at a new drug called J7, which is based on curcumin, a natural compound found in turmeric, to see if it could help protect the liver and improve sugar and fat metabolism. We used a rat model of type 2 diabetes to test J7. Rats were given either curcumin, a low dose of J7, or a high dose of J7. We then measured how well their livers were working and examined their liver tissue under a microscope. We also looked at the levels of specific molecules in the liver that are involved in inflammation, scarring, and cell survival. We found that J7 worked better than regular curcumin. It reduced liver damage, improved how the liver handled sugar and fat, and lessened scarring. J7 achieved this by affecting certain biological pathways, like the TGF-β/Smad pathway and NF-κB signaling, which are key players in liver damage and inflammation. These results suggest that J7 could be a promising new treatment for liver problems in people with diabetes. This study highlights the potential of improving natural compounds like curcumin to make them more effective as medicines. Further research is needed to explore how J7 might help people with diabetes and liver issues.Keywords: insulin resistance, metabolic dysfunction-associated fatty liver disease, MAFLD, curcumin analog, liver fibrosis, TGF-β/Smad signaling pathway, NF-κB-BCL-2/BAX axis