Shugan Xiaozhi Formula Reduces Hepatic Steatosis and Stiffness in MASLD Patients with Elevated ALT: An Exploratory 24-Week Randomized Trial

BACKGROUND: Metabolic dysfunction-related fatty liver disease (MASLD) affects approximately one-third of adults worldwide. The most common manifestations in the early stage are liver dysfunction, hepatic steatosis，metabolic abnormalities, and obesity. The failure of single behavioral interventions and the limited availability of treatment drugs remain unmet clinical needs. METHODS: In this 24-week, multicenter, prospective, randomized, open-label, active-controlled, proof-of-concept trial conducted in China, 285 participants with MASLD (ALT >40U/L to 5×ULN) were randomly assigned in a 1:1 ratio to receive Shugan Xiaozhi Formula (SGXZ) granules or vitamin E 300mg/day. The primary exploratory endpoints were changes in hepatic steatosis measured by MRI-proton density fat fraction (MRI-PDFF) and FibroScan-controlled attenuation parameter (CAP), and changes in liver stiffness by transient elastography (TE) and magnetic resonance elastography (MRE). Additional outcomes included liver enzymes, anthropometric measures, and safety parameters. Analyses were performed in the completer population (n=152) using ANCOVA and logistic regression. RESULTS: At week 24, SGXZ significantly reduced MRI-PDFF (adjusted mean difference vs vitamin E, -3.44 percentage points; 95% CI, -5.18 to -1.69; P<0.001) and CAP (-45.42dB/m; 95% CI, -58.37 to -32.47; P<0.001). A higher proportion of SGXZ recipients achieved a ≥1-category reduction in MRI-PDFF-defined steatosis grade (22.4% vs 5.3%; OR, 5.83; P=0.007) and a ≥30dB/m reduction in CAP (82.9% vs 39.5%; OR, 8.01; P<0.001). Liver stiffness parameters also improved more with SGXZ (TE, -1.14 kPa; P<0.001; MRE, -0.06m/s; P<0.001). Changes in ALT and AST did not differ between groups, whereas GGT normalization was more frequent with SGXZ (52.3% vs 27.7%; OR, 2.87; P=0.010). SGXZ was also associated with significantly greater reductions in body weight (between-group mean difference, -2.69kg; 95% CI, -3.60 to -1.78; P < 0.001), BMI (-0.94kg/m²; 95% CI, -1.26 to -0.62; P < 0.001), and WHR (-0.04; 95% CI, -0.08 to -0.01; P = 0.020). SGXZ was generally well tolerated; gastrointestinal events were more common but were mild and self-limiting. No serious adverse events or clinically meaningful laboratory safety signals occurred. CONCLUSIONS: In this exploratory trial, SGXZ was associated with greater reductions in hepatic steatosis, imaging-based liver stiffness, body weight, BMI, and WHR than vitamin E, with an acceptable safety profile. These findings suggest that SGXZ represents a highly promising compound natural medicine therapeutic option for the complex metabolic diseases MASLD/MASH. It meets the urgent clinical need for safe and effective therapies to comprehensively improve patients' conditions. Of course, these findings require further validation in large-scale trials with sufficient statistical power. CLINICAL TRIAL REGISTRATION NUMBER: ChiCTR2200057595.