Synthesis and anti-liver fibrotic activity study of a chalcone derivative through anti-inflammatory effects and inhibition of JNK/NF-κB signaling pathways.

Liver fibrosis is a progressive disease caused by chronic inflammation and the activation of hepatic stellate cells (HSCs). This disease manifests as the abnormal proliferation and migration of HSCs, as well as the excessive deposition of the extracellular matrix. Chalcone analogues exhibit various biological activities, including anti-inflammatory, anti-proliferative, and apoptotic modulation properties, making them promising candidates for anti-fibrotic drug development. To enhance anti-fibrotic activities and decrease their side-effects, 31 novel chalcone derivatives were synthesized and evaluated. Among all the compounds, c31 exhibited the strongest anti-inflammatory activity, and its IC50 is 3.05 ± 0.12 µM; and it effectively inhibited the activation and proliferation of HSC-T6 cells. Mechanistic studies revealed that c31 inhibits HSC activation by downregulating the expression levels of inflammatory factors, such as TNF-α, IL-6, and IL-1β, and by interfering with NF-κB and JNK signaling pathways. Additionally, c31 inhibited HSC-T6 proliferation and promoted apoptosis by blocking a G2/M phase cell cycle; and it also significantly inhibited HSC-T6 cell migration. In a rat model of CCl₄-induced liver fibrosis, c31 improved pathological symptoms, decreasing collagen deposition, fibrotic protein expression, and ALT and AST levels. Meanwhile, it also reduced the secretion of inflammatory factors, thereby alleviating CCl₄-induced liver fibrosis. In summary, c31 had significant anti-inflammatory and anti-fibrotic effects in both in vivo and in vitro; this indicates c31 has the potential to be used as a therapeutic candidate for hepatic inflammation and fibrosis.