Study Objective: To evaluate the efficacy and safety of Rifaximin-α in the treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), and investigate the underlying mechanisms by which Rifaximin-α influences MASLD progression.

Target Population: Patients diagnosed with MASLD. Intervention: This trial is a multicenter, prospective, randomized, controlled study. Enrolled MASLD patients who meet the inclusion criteria, do not meet any exclusion criteria, and provide written informed consent will be randomized in a 2:1 ratio to the Rifaximin-α treatment group (40 cases) or the control group (20 cases). All patients are advised to maintain daily physical activity and follow a recommended dietary plan (e.g., Mediterranean diet). The Rifaximin-α treatment group will receive oral Rifaximin-α at a dose of 1200 mg per day for 24 weeks. Both groups of patients will enter a 24-week follow-up period after completing the 24-week treatment. During the study, patients' existing foundational treatments (such as liver-protecting, lipid-lowering, glucose-lowering, and antihypertensive therapies) will be maintained. Relevant indicators will be closely monitored. And avoid the use of medications known to alter the gut microbiota, such as lactulose, antibiotics, and various types of intestinal microecological preparations.

Investigational Drug: Rifaximin-α (Alfa Wassermann S.p.A., Italy).

Inclusion Criteria

1. Willingness to provide written informed consent.

2. Aged 18 to 75 years, inclusive, regardless of gender.

3. Diagnosis of hepatic steatosis (fatty liver) within the past 6 months.

4. Presence of at least one metabolic/cardiovascular risk factor:

   A. BMI ≥ 23.0 kg/m², or waist circumference ≥ 90 cm (male) / 80 cm (female). B. Fasting plasma glucose (FPG) ≥ 5.6 mmol/L, or 2-hour postprandial glucose ≥ 7.8 mmol/L, or HbA1c ≥ 5.7%, or documented history of type 2 diabetes mellitus (T2DM) or current use of anti-diabetic medication.

   C. Fasting serum triglycerides (TG) ≥ 1.70 mmol/L, or current use of medication for hypertriglyceridemia.

   D. Serum high-density lipoprotein (HDL) cholesterol ≤ 1.0 mmol/L (male) and ≤ 1.3 mmol/L (female), or current use of lipid-lowering medication.

   E. Blood pressure ≥ 130/85 mmHg, or current use of antihypertensive medication.

5. Liver fat content ≥ 8% as measured by Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF).

Exclusion Criteria

1. Confirmed diagnosis of liver cirrhosis based on clinical, laboratory, imaging, and/or liver biopsy findings.
2. Evidence of other specific etiologies of chronic liver disease confirmed by history or laboratory tests, including but not limited to: viral hepatitis (B or C, etc.), autoimmune liver disease, alcohol-related liver disease (defined as >20 g/day for females or >30 g/day for males), drug-induced liver injury, Wilson's disease, alpha-1 antitrypsin deficiency, or hereditary hemochromatosis.
3. Other identifiable causes of hepatic steatosis confirmed by history or laboratory tests, such as: specific medications (e.g., tamoxifen, amiodarone, valproate, methotrexate, glucocorticoids, olanzapine), total parenteral nutrition, hypothyroidism, inflammatory bowel disease, Cushing's syndrome, celiac disease, abetalipoproteinemia, lipodystrophic diabetes, Mauriac syndrome, hypopituitarism, hypogonadism, polycystic ovary syndrome, etc.
4. Use of medications known to alter gut microbiota (e.g., lactulose, systemic antibiotics, any intestinal microecological preparations) within 4 weeks prior to screening.
5. Dose of hepatoprotective or lipid-lowering medications not stabilized for at least 4 weeks prior to screening.
6. Received any Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or remeglutide treatment within 12 weeks prior to screening, or plans to receive such treatment during the study.
7. Dose of medications that may affect MASLD, anti-diabetic agents (excluding GLP-1 RAs and remeglutide), or weight-loss drugs not stabilized for at least 12 weeks prior to screening.
8. Self-reported weight change >5% within 4 weeks prior to screening.
9. BMI > 35 kg/m².
10. Poorly controlled glycemia: HbA1c > 9%.
11. Total bilirubin > 1.5 mg/dL (except with normal direct bilirubin), or Alanine Aminotransferase (ALT) > 5 times the Upper Limit of Normal (ULN), or Aspartate Aminotransferase (AST) > 5 times ULN, or Alkaline Phosphatase (ALP) > 2 times ULN.
12. Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min/1.73 m².
13. History of or planned bariatric/metabolic therapy, including but not limited to endoscopic interventions, surgical procedures, or Traditional Chinese Medicine therapies. Exceptions may be made if previous interventions have been reversed or removed (e.g., intragastric balloon, subcutaneous threads) for more than 12 weeks.
14. History of or current hepatocellular carcinoma (HCC).
15. Diagnosis of any malignancy within the past 5 years, except for malignancies with low risk of metastasis or death (estimated 5-year overall survival >90%), such as effectively treated early-stage gastrointestinal cancer, carcinoma in situ of the cervix, non-melanoma skin cancer, or localized prostate cancer.
16. Significant comorbid conditions affecting the cardiovascular, respiratory, rheumatological/immunological, hematological, biliary, or pancreatic systems; or history of myocardial infarction, stroke, heart failure, unstable angina, or transient ischemic attack within 6 months prior to screening; or presence of psychiatric disorders.
17. HIV infection.
18. Known allergy or hypersensitivity to rifaximin.
19. Contraindications to MRI, such as incompatible metallic implants, claustrophobia, or body size exceeding scanner capacity.
20. Pregnant or lactating women, women of childbearing potential not using effective contraception, or individuals planning pregnancy.
21. Participation in another investigational drug trial within 3 months prior to screening.
22. Any other condition deemed by the investigator to be unsuitable for participation in the study.