Annals of hepatology · 2025
Naringenin attenuates early hepatocarcinogenesis induced by a MASH model.
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Márquez-Quiroga Linda Vanessa, Barboza-López Aline, Suárez-Castillo Jose Y, Cardoso-Lezama Irina, Fuentes-Figueroa Miguel Á, Vargas-Pozada Eduardo E, Rodriguez-Callejas Juan D, Ramos-Tovar Erika, Piña-Vázquez Carolina, Arellanes-Robledo Jaime, Villa-Treviño Saúl, Muriel Pablo
Аннотация
INTRODUCTION AND OBJECTIVES: Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in the progression of metabolic dysfunction-associated steatohepatitis (MASH). Here, we investigated the effects of naringenin (NAR) on early hepatocellular carcinoma (HCC) experimentally induced in a rat MASH model and whether the NLRP3 inflammasome/pyroptosis pathway was involved.
MATERIALS AND METHODS: The animals were fed a hepatopathogenic diet for 16 weeks and carbon tetrachloride (400 mg/kg, i.p.) and diethylnitrosamine (40 mg/kg, i.p.) were injected once a week. NAR was administered at 100 mg/kg p.o. The effects of NAR on the MASHHCC protocol were evaluated using biochemical, histological, in silico, and molecular biological approaches.
RESULTS: NAR significantly mitigated liver damage, as evidenced by the reduction in liver damage markers. It also reduced steatosis and inflammation, as determined by decreased lipid accumulation and sterol regulatory element-binding protein 1C, interleukins 1-beta and 18, and nuclear factor kappa B levels, and also increased peroxisome proliferator-activated receptor gamma levels. NAR inhibits the formation of NLRP3, including the recruitment of caspase-1 and gasdermin D proteins, and reduces the levels of transforming growth factor-beta, alpha-smooth muscle actin, and hepatic collagen 1, thereby diminishing extracellular matrix synthesis. Furthermore, gamma-glutamyl transpeptidase activity, glutathione S-transferase pi 1, and the proliferation marker KI67 were considerably reduced.
CONCLUSIONS: Our findings show that NAR has the potential to inhibit early HCC induced in the context of MASH, thereby suggesting that NAR could be used for MASH treatment in humans.
MATERIALS AND METHODS: The animals were fed a hepatopathogenic diet for 16 weeks and carbon tetrachloride (400 mg/kg, i.p.) and diethylnitrosamine (40 mg/kg, i.p.) were injected once a week. NAR was administered at 100 mg/kg p.o. The effects of NAR on the MASHHCC protocol were evaluated using biochemical, histological, in silico, and molecular biological approaches.
RESULTS: NAR significantly mitigated liver damage, as evidenced by the reduction in liver damage markers. It also reduced steatosis and inflammation, as determined by decreased lipid accumulation and sterol regulatory element-binding protein 1C, interleukins 1-beta and 18, and nuclear factor kappa B levels, and also increased peroxisome proliferator-activated receptor gamma levels. NAR inhibits the formation of NLRP3, including the recruitment of caspase-1 and gasdermin D proteins, and reduces the levels of transforming growth factor-beta, alpha-smooth muscle actin, and hepatic collagen 1, thereby diminishing extracellular matrix synthesis. Furthermore, gamma-glutamyl transpeptidase activity, glutathione S-transferase pi 1, and the proliferation marker KI67 were considerably reduced.
CONCLUSIONS: Our findings show that NAR has the potential to inhibit early HCC induced in the context of MASH, thereby suggesting that NAR could be used for MASH treatment in humans.