Amlodipine and perindopril modulate miR-874-3p expression to regulate ferroptosis-linked LPCAT3/LACS4/GPX4 Axis and gut dysbiosis in metabolic-associated steatohepatitis.

Introduction: Metabolic dysfunction-associated fatty liver disease (MAFLD) and its advanced form, metabolic-associated steatohepatitis (MASH), are significant contributors to chronic liver disease. Iron overload, ferroptosis, and intestinal permeability disruptions are critical drivers requiring targeted therapies.

Aim: This study evaluated the therapeutic effects of amlodipine and perindopril on ferroptosis and intestinal barrier integrity in a diet-induced MASH model and elucidated their mechanistic roles in modulating the miR-874-3p/LPCAT3/LACS4/GPX4 axis identified via bioinformatics.

Methods: Male Wistar rats were divided into Sham (normal diet), MASH (high-fat, high-sugar diet), Amlo (MASH + amlodipine), Peri (MASH + perindopril), and Amlo+Peri (combination therapy) groups. Experiments included serum lipid and liver function assays, qPCR for ferroptosis markers (miR-874-3p, LPCAT3, LACS4, GPX4), and evaluation of intestinal permeability (zonulin, TMAO) and occludin expression via immunohistochemistry. Hepatic inflammatory (IL-6), fibrotic (TGF-β1), and apoptotic (caspase-3) markers were analyzed alongside liver and intestinal histopathology.

Results: Both treatments effectively improved liver function and lipid profiles while reducing inflammatory, fibrotic, and apoptotic markers in MASH rats. Histopathological analysis demonstrated significant reductions in hepatic steatosis, fibrosis, inflammation, and iron deposition. Ferroptosis-related markers showed significant modulation: GPX4 and miR-874-3p were upregulated, while LPCAT3 and LACS4 were downregulated. Intestinal barrier function improved, evidenced by increased intestinal occludin expression and decreased serum zonulin and TMAO levels. Combination therapy exhibited the strongest effects across all parameters.

Conclusion: Amlodipine and perindopril, particularly in combination, effectively modulate the miR-874-3p/LPCAT3/LACS4/GPX4 axis to address ferroptosis and gut dysfunction in MASH, offering promising therapeutic avenues.