Hepatoprotective Effects of Fused Pyridine Derivatives: Regulation of the TGF-β/Smad, miR-21/Smad7, and PPARγ Pathways in Carbon Tetrachloride-Induced Liver Fibrosis

Background: The liver functions as the body’s central metabolic organ, responsible for a wide array of vital processes, making its protection a key objective in medical research. Consequently, the promising hepatoprotective potential of several 4-phenyltetrahydroquinoline derivatives motivated us to comprehensively investigate the mechanisms of action of four newly synthesized compounds on carbon tetrachloride (CCl 4 )-induced liver injury in rats. Methods: Liver tissues and serum samples were collected from all experimental groups of Sprague-Dawley rats for histopathological examination, serological testing, RT-PCR, and ELISA. The mRNA expression levels of TGF-β, Smad2, α-SMA, Col1a1, Smad7, miR-21, and PPARγ, along with the protein levels of MMP-9 and TGF-β, were analyzed in liver tissues. Additionally, the HepG2 cell line was used for in vitro hepatotoxicity testing. Results: The mRNA expression of miR-21, Smad2, α-SMA, Col1A1, and TGF-β, as well as the protein levels of TGF-β and MMP-9, was reduced in rats treated with our compounds compared to CCl 4 -induced liver fibrosis in adult male Sprague-Dawley rats. Conversely, these compounds increased the mRNA expression of Smad7 and PPARγ. Additionally, the histopathological analysis showed a decrease in the degree of liver fibrosis following treatment with the tested compounds. Conclusion: The tested fused pyridine derivatives may protect the liver from fibrosis by modulating the TGF-β/Smad, miR-21-regulated TGF-β/Smad7, and PPARγ signaling pathways. These findings suggest that these derivatives could serve as novel agents for protecting the liver against fibrosis. Keywords: liver fibrosis, 4-phenyltetrahydroquinoline derivatives, rats, hepatotoxicity, CCl 4 , TGF-β, Smad, PPARγ, miR-21