Orphan drug uttroside B impedes MASH progression and HCC development in experimental models

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury, ultimately triggering chronic conditions, including fibrosis and cirrhosis, which may progress to hepatocellular carcinoma (HCC). Uttroside B (Utt-B), a phytosaponin isolated in our lab, has gained global recognition owing to its anti-HCC potential and is currently a United States FDA-designated 'orphan drug' against HCC. The present study highlights Utt-B as a propitious candidate drug against MASH and MASH-induced HCC.

MASH and MASH-induced HCC were developed in C57BL/6J mice using two distinct murine models: a high-fat diet model and a streptozotocin-induced steatohepatitis-derived HCC model, followed by i.p. administration of Utt-B. Protein expression analysis was performed using real-time quantitative reverse transcription-PCR and immunoblotting, while H&E, Oil Red O, Sirius Red, and Masson's Trichrome were utilized for staining cells/tissues. Nanostring n-Counter analysis was used to investigate the mechanism underlying the antifibrotic effects of Utt-B in MASH-induced HCC. Proliferation and apoptosis markers were also evaluated. Statistical analyses were conducted using R and GraphPad-Prism with significance set at p <0.05.

Utt-B ameliorated MASH-associated pathological features, including steatosis, hepatocyte ballooning, and inflammation (N = 6; non-alcoholic fatty liver disease activity score [NAS] <2, p <0.0001). Utt-B upregulated the expression of autophagy markers autophagy-related 7 (ATG-7), Beclin-1, and microtubule-associated protein 1A/1B-light chain (LC3-II), and downregulated the expression of α-smooth muscle actin (α-SMA), which indicates the activation of hepatic stellate cells. Utt-B also halted the progression of MASH to HCC by hindering development of fibrosis with simultaneous inhibition of proliferative signals and induction of apoptosis in murine models (N = 6; NAS <3, p <0.01).

Our investigation revealed effective impedance of MASH and its concomitant progression to HCC by Utt-B. Given the lack of anti-MASH drugs, these findings establish Utt-B as a potent drug for treating MASH and MASH-induced HCC.

MASH, stage IV of non-alcoholic fatty liver disease, can lead to chronic conditions, including fibrosis and cirrhosis, elevating the risk of HCC. Impaired lipid metabolism, inflammation, inhibition of autophagy, and dysregulated collagen and extracellular matrix biosynthesis are key factors contributing to the advance of MASH to HCC. Our discovery of Utt-B, a phytosaponin that exhibits remarkable anti-HCC potential and is a United States FDA-designated orphan drug against HCC, has gained global recognition. The present study reveals Utt-B as a propitious candidate drug against MASH and MASH-induced HCC in a high-fat diet murine model and streptozotocin-induced steatohepatitis-derived HCC animal model, respectively.