Oxidative stress (OS) contributes to nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. We investigated whether antioxidative self-assembling nanoparticles (SMAPo
TN) could reduce the development of NASH and hepatocellular carcinoma (HCC) in
p62/Sqstm1 and
Nrf2 double knockout (DKO) mice and studied protective mechanisms. We measured
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Oxidative stress (OS) contributes to nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. We investigated whether antioxidative self-assembling nanoparticles (SMAPo
TN) could reduce the development of NASH and hepatocellular carcinoma (HCC) in
p62/Sqstm1 and
Nrf2 double knockout (DKO) mice and studied protective mechanisms. We measured disease development in male DKO mice fed a normal chow (NASH model) or a 60% high-fat diet (HFD; HCC model) with or without SMAPo
TN administration for 26 weeks. SMAPo
TN inhibited liver fibrosis in both groups and prevented HCC development (0% vs. 33%,
p < 0.05) in the HFD group. SMAPo
TN reduced OS, inflammatory cytokine signaling, and liver fibrosis. RNA-sequencing revealed that SMAPo
TN decreased endoplasmic reticulum stress signaling genes in both groups, HCC driver genes, and cancer pathway genes, especially PI3K-AKT in the HFD groups. In the SMAPo
TN treatment HFD group, serum lipopolysaccharide levels and liver lipopolysaccharide-binding protein expression were significantly lower compared with those in the nontreatment group. SMAPo
TN improved the α-diversity of gut microbiota, and changed the microbiota composition. Oral SMAPo
TN administration attenuated NASH development and suppressed hepatocarcinogenesis in DKO mice by improving endoplasmic reticulum stress in the liver and intestinal microbiota. SMAPo
TN may be a new therapeutic option for NASH subjects and those with a high HCC risk.
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