Targeting early events in hepatocarcinogenesis: anti-inflammatory and SIRT1-mediated effects of 6-Gingerol in a murine model

Background: Persistent inflammation, compensatory cell proliferation, and gene regulation through epigenetic modifications are frequently linked to hepatocellular carcinoma (HCC) development. Therefore, natural compounds that can suppress inflammatory processes are vital in improving the pathogenesis of diseases triggered by chronic inflammation. Although Sirtuin-1—a nuclear sirtuin known for its anti-inflammatory roles in diverse tissues and cells including macrophages—has gained interest, its specific contribution in HCC remains insufficiently explored. Methods: This study employed a mouse model to induce liver cancer using diethylnitrosamine (DEN) and 2-acetylaminofluorene (2AAF). A total of forty male BALB/c mice, weighing around 18 ± 2 g, were divided to four groups of ten. Group 1 was orally treated with a dose of corn oil, while Group 2 received a single intraperitoneal dose of DEN at 75 mg/kg, followed by 2AAF at 200 mg/kg dietary plan. Meanwhile, Group 3 was solely treated with 6-gingerol at 100 mg/kg. Lastly, Group 4 received 6-gingerol for 7 days prior to DEN + 2AAF exposure, with treatment maintained for 20 weeks. Results: Administration of 6-gingerol conferred protective effects in HCC-induced mice by lowering the levels of TNF-α, IL-1β, COX-2, and iNOS. Its anti-inflammatory potential was further demonstrated through reduced expression of NF-κB and BCL2 in liver tissues, alongside increased levels of p53 and SIRT-1. Conclusion: The findings suggest that 6-gingerol counteracts DEN+2AAF-induced liver cancer by downregulating inflammatory mediators and promoting apoptosis through SIRT-1 activation.