Flaxseed Oil Inhibits Hepatic Preneoplastic Lesions, DNA Damage, and γ-H2AX Expression During Initial Phases of Hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is often diagnosed at advanced stages, limiting therapeutic options. Therefore, preventive strategies are crucial for its control. Among these, the use of nutrients and bioactive food compounds, such as omega-3 polyunsaturated fatty acids (n-3 PUFAs), has gained attention. Alpha-linolenic acid (ALA), a plant-derived n-3 PUFA abundant in flaxseed oil (FSO), has shown chemopreventive effects in various cancer models. This study investigated the chemopreventive potential of FSO in rats subjected to the resistant hepatocyte (RH) model of hepatocarcinogenesis, which generates preneoplastic lesions that may either progress to HCC (pPNL) or revert to a normal phenotype (rPNL). FSO treatment led to a reduction in the number of liver nodules and decreased both the number and size of pPNL. These effects were associated with increased hepatic ALA levels. FSO did not affect cell proliferation or apoptosis; however, it reduced DNA damage and inhibited γ-H2AX expression in preneoplastic livers, particularly in pPNL. Given that pPNL shares molecular alterations with HCC, the inhibition of γ-H2AX suggests a relevant mechanism by which FSO contributes to the chemoprevention of hepatocarcinogenesis.