Figure 5.

Semaglutide and lanifibranor differentially improves NASH histological hallmarks in GAN DIO-NASH-HCC mice. GAN DIO-NASH-HCC mice with biopsy-confirmed NASH and fibrosis were administered (QD) vehicle (SC), semaglutide (30 nmol/kg, SC) or lanifibranor (mg/kg, PO) for 14 weeks (n = 15–16 per group). Treatment was initiated after 54 weeks of GAN diet feeding. Mice were stratified/randomized to treatment according to severity of NASH (NAS ≥ 5) and fibrosis (fibrosis stage F3) assessed 4 weeks before treatment start. Chow-fed mice receiving (QD) saline vehicle for 14 weeks (Chow + Vehicle) served as normal controls (n = 10). (A) NAFLD Activity Score (NAS) and fibrosis stage. (B) Steatosis score, lobular inflammation score and ballooning degeneration score. *p < 0.05, **p < 0.01, ***p < 0.001 (one-sided Fisher’s exact test with Bonferroni correction). See Fig. S8 for changes in histopathological scores in individual mice. (C-G) Histomorphometric assessment of histopathological scoring variables as determined by the AI-based GHOST application. (C) Proportionate area (%) of hepatocytes with lipid droplets. (D) Number of inflammatory foci per mm². (E) Hepatocyte ballooning (cells/mm²). (F, G) % area of sinusoidal fibrosis and periportal fibrosis. **p < 0.01, ***p < 0.001 vehicle-dosed GAN DIO-NASH mice; ^#p < 0.05 versus semaglutide (Dunnett’s test one-factor linear model). (H) Representative photomicrographs illustrating reduced steatosis (HE staining) after semaglutide and lanifibranor treatment. Scale bar, 100 µm.