Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease.

Background: Prevalence of hepatocellular carcinoma (HCC) is increasing, especially in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Aim: To investigate rifaximin (RIF) effects on epigenetic/autophagy markers in animals.

Methods: Adult Sprague-Dawley rats were randomly assigned ( = 8, each) and treated from 5-16 wk: Control [standard diet, water plus gavage with vehicle (Veh)], HCC [high-fat choline deficient diet (HFCD), diethylnitrosamine (DEN) in drinking water and Veh gavage], and RIF [HFCD, DEN and RIF (50 mg/kg/d) gavage]. Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.

Results: All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis, and cirrhosis, but three RIF-group did not develop HCC. Comparing animals who developed HCC with those who did not, miR-122, miR-34a, tubulin alpha-1c , metalloproteinases2 , and metalloproteinases9 were significantly higher in the HCC-group. The opposite occurred with , coactivator associated arginine methyltransferase-1 (), enhancer of zeste homolog-2 (), autophagy-related factor LC3A/B , and sequestosome-1 (SQSTM1protein Comparing with controls, , and were lower in HCC and RIF-groups ( < 0.05). was lower in HCC compared to RIF ( < 0.05). Hepatic expression of was higher in HCC in relation to the control; the opposite was observed for ( < 0.05). Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control ( = 0.024). There was no difference among groups for , Aldolase-B, alpha-fetoprotein, and ( > 0.05). miR-122 was higher in HCC, and miR-34a in RIF compared to controls ( < 0.05). miR-26b was lower in HCC compared to RIF, and the inverse was observed for miR-224 ( < 0.05). There was no difference among groups regarding miR-33a, miR-143, miR-155, miR-375 and miR-21 ( > 0.05).

Conclusion: RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.