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

Area of Science:

• Hepatology and Gastroenterology
• Pharmacology and Drug Discovery
• Oncology

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a severe liver condition characterized by fat accumulation, inflammation, and injury, potentially leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).
• Current therapeutic options for MASH are limited, creating an urgent need for effective treatments.
• Uttroside B (Utt-B), a phytosaponin with recognized anti-HCC properties and FDA orphan drug designation, is explored for its potential against MASH.

Purpose of the Study:

• To investigate the efficacy of Uttroside B (Utt-B) in ameliorating MASH and preventing MASH-induced hepatocellular carcinoma (HCC).
• To elucidate the underlying mechanisms of Utt-B's antifibrotic and anti-cancer effects in MASH models.

Main Methods:

• Murine models of MASH and MASH-induced HCC were established using a high-fat diet and a streptozotocin-induced model.
• Utt-B was administered intraperitoneally, and its effects were assessed through histological analysis (H&E, Oil Red O, Sirius Red, Masson's Trichrome), protein expression (RT-qPCR, immunoblotting), and Nanostring n-Counter analysis.
• Evaluation of proliferation and apoptosis markers was conducted, with statistical analyses performed using R and GraphPad-Prism.

Main Results:

• Utt-B significantly ameliorated MASH pathological features, including steatosis, hepatocyte ballooning, and inflammation (NAS <2, p <0.0001).
• Utt-B upregulated autophagy markers (ATG-7, Beclin-1, LC3-II) and downregulated α-SMA, indicating reduced hepatic stellate cell activation.
• Utt-B inhibited MASH progression to HCC by hindering fibrosis, suppressing proliferation, and inducing apoptosis (NAS <3, p <0.01).

Conclusions:

• Uttroside B demonstrates significant therapeutic potential for MASH and MASH-induced HCC.
• Utt-B effectively reverses MASH pathology and halts its progression to cancer by modulating autophagy, fibrosis, and cell death pathways.
• These findings position Utt-B as a promising drug candidate for treating MASH and associated liver cancer, addressing a critical unmet medical need.