📖 ABSTRACT/OVERVIEW
Hepatocellular carcinoma (HCC) driven by aflatoxin B1 (AFB1) contamination of staple foods constitutes one of the most serious cancer threats in Nigeria, where groundnuts, maize, and sorghum consumed across all geopolitical zones are frequently contaminated above WHO safe limits. Kolaviron, a biflavonoid complex from Garcinia kola seeds, has demonstrated hepatoprotective and anticarcinogenic properties in preliminary studies. This research systematically investigates the mechanistic basis of kolaviron's hepatoprotection against AFB1-induced hepatocarcinogenesis through integrated epigenetic, oxidative stress, and oncogenic signalling pathway analysis in a long-term rat carcinogenesis model. AFB1-induced hepatocarcinogenesis was initiated over 20 weeks in Wistar rats with kolaviron co-treatment at 100 and 200 mg/kg. Hepatotoxicity progression was monitored by serial liver enzyme profiling, AFP serum levels, and hepatic imaging. Mechanistic investigations included: DNA methylation profiling of hepatic tumour suppressor loci by bisulphite pyrosequencing, Nrf2-Keap1 pathway activation analysis by Western blot, NF-kB and PI3K-Akt-mTOR signalling protein expression, and transcriptomic analysis by RNA-Seq. Kolaviron co-treatment significantly delayed tumour nodule development, reduced serum AFP elevation, and attenuated DNA methylation-based silencing of RASSF1A and p53. Nrf2 nuclear translocation was significantly enhanced, reducing oxidative DNA damage markers. NF-kB and mTOR activation were markedly suppressed. RNA-Seq identified 312 differentially expressed genes in kolaviron-treated animals versus AFB1 controls, enriched in DNA repair and detoxification pathways. These findings establish multi-pathway mechanistic hepatoprotective evidence for kolaviron against AFB1-induced HCC. Keywords: kolaviron, aflatoxin B1, hepatocarcinogenesis, Nrf2, epigenetic
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