Michalczuk Matheus Truccolo, Longo Larisse, Keingeski Melina Belén, Basso Bruno de Souza, Guerreiro Gabriel Tayguara Silveira, Ferrari Jessica T, Vargas José Eduardo, Oliveira Cláudia P, Uribe-Cruz Carolina, Cerski Carlos Thadeu Schmidt, Filippi-Chiela Eduardo, Álvares-da-Silva Mário Reis
Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil.
Graduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-003, Rio Grande do Sul, Brazil.
World J Hepatol. 2024 Jan 27;16(1):75-90. doi: 10.4254/wjh.v16.i1.75.
Prevalence of hepatocellular carcinoma (HCC) is increasing, especially in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).
To investigate rifaximin (RIF) effects on epigenetic/autophagy markers in animals.
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.
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).
RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.
肝细胞癌（HCC）的患病率正在上升，尤其是在代谢功能障碍相关脂肪性肝病（MASLD）患者中。
研究利福昔明（RIF）对动物表观遗传/自噬标志物的影响。
将成年Sprague-Dawley大鼠随机分组（每组n = 8），并在5至16周进行治疗：对照组[标准饮食，饮用水加赋形剂（Veh）灌胃]，HCC组[高脂胆碱缺乏饮食（HFCD），饮用水中添加二乙基亚硝胺（DEN）并进行Veh灌胃]，以及RIF组[HFCD，DEN和RIF（50 mg/kg/d）灌胃]。获取表观遗传/自噬标志物的基因表达和循环miRNA。
所有HCC组和RIF组动物均发生了代谢功能障碍相关脂肪性肝炎纤维化和肝硬化，但RIF组中有3只未发生HCC。将发生HCC的动物与未发生HCC的动物进行比较，HCC组中的miR-122、miR-34a、微管蛋白α-1c、金属蛋白酶2和金属蛋白酶9显著更高。而在自噬相关因子LC3A/B、聚集体蛋白1（SQSTM1蛋白）方面则相反。与对照组相比，HCC组和RIF组中的自噬相关因子、共激活因子相关精氨酸甲基转移酶-1（CARM1）、zeste同源物2（EZH2）较低（P < 0.05）。与RIF组相比，HCC组中的自噬相关因子更低（P < 0.05）。与对照组相比，HCC组中自噬相关因子的肝脏表达更高；而对于EZH2则观察到相反情况（P < 0.05）。与对照组相比，RIF组中p62/SQSTM1蛋白的表达更低（P = 0.024）。各组之间在自噬相关因子、醛缩酶-B、甲胎蛋白和方面无差异（P > 0.05）。与对照组相比，HCC组中的miR-122更高，RIF组中的miR-34a更高（P < 0.05）。与RIF组相比，HCC组中的miR-26b更低，而miR-224则相反（P < 0.05）。各组之间在miR-33a、miR-143、miR-155、miR-375和miR-21方面无差异（P > 0.05）。
在MASLD-HCC大鼠模型中，RIF可能通过表观遗传调节对预防/延缓肝癌发生具有潜在的有益作用。
