Yujing Wang,Yuanxin Xu,Yilin Liu,Jindan Lin,Xincai Hong,Shuang Yan
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global disease with a broad spectrum of symptoms. Pirin (PIR) is involved in a variety of biological and molecular processes. However, the role of PIR in MASLD remains unclear. Rats were fed with high-fat and high-cholesterol (HFC) diet to induce MASLD. Time-course results showed that liver in HFC-fed rats exhibited a progressive increase in hepatic tissue damage over time (3, 6, and 9 weeks), and developed in obvious hepatic fibrosis and steatosis at week 9. Meanwhile, HFC feeding also gradually increased PIR expression in liver. In vitro , PIR expression was up-regulated in palmitic acid (PA)-induced Hep3B cells. PIR knockdown using PIR shRNA plasmid inhibited steatosis and expression of ACLY, FASN, and XBP1 in PA-induced Hep3B cells. Knocking down PIR inhibited hepatocyte inflammation by inhibiting phosphor-NF-κB p65 into the nucleus, which inhibited the expression of TNF-α and IL-1β. In MASLD, hepatocyte inflammation activates hepatic stellate cell, thereby leading to hepatic fibrosis. Supernatant from PA-treated Hep3B with PIR knockdown inhibited LX-2 activation, as evidenced by decreased expression of Col1A1 and α-SMA in LX-2 cells. Together, these results suggested that PIR knockdown might alleviate the progression of MASLD by inhibiting liver lipid deposition and inflammation, further inhibiting liver fibrosis. Transcriptome data analysis suggested that alteration in the expression of lipid metabolism-related pathways and genes might be a potential cause of PIR regulation in MASLD progression. These findings may reveal a novel target for MASLD therapy.
Glycyrrhetinic acid (GA) is a naturally occurring triterpene compound. The aim of this study was to employ the pharmacophore hybrid strategy to merge GA with various dithiocarbamates and obtain novel compounds with better antitumor activities. We present a two-step synthetic protocol wherein the GA derivative underwent reaction with carbon disulfide and various secondary amines in a one-pot manner under mild conditions, facilitating the preparation of a series of structurally novel GA-dithiocarbamate derivatives. Bioassay screening revealed that the representative compound 3c demonstrated the capacity to reduce the mitochondrial membrane potential in Hep3B and Huh-7 cells, induce nuclear apoptosis, inhibit invasion and migration, and prompt both early and late apoptosis. Furthermore, our research findings indicated that this apoptotic phenomenon may be associated with the expression of Bcl-2, Bax, Bak, PARP, and cleaved-PARP proteins. Utilizing network pharmacology for predicting core targets and signaling pathways of compound 3c for hepatocellular carcinoma (HCC) treatment involved employing molecular docking models to demonstrate high affinity between compound and target protein. In conjunction with Western blot analysis, compound 3c may impact HCC through the PI3K-AKT-mTOR pathway.
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