Targeting mTOR with vistusertib attenuates metabolic steatohepatitis and prevents HCC development

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disorder characterised by lipid accumulation, leading to inflammation, hepatocellular injury, varying degrees of fibrosis, and ultimately hepatocellular carcinoma (HCC). Despite recent advances in drug discovery (approval of resmetirom and semaglutide), MASH remains an unmet medical need, highlighting the need for new therapies to halt disease progression and prevent complications such as HCC. This study aimed to investigate the therapeutic effect of the mTORC1/2 inhibitor (vistusertib) against the spectrum of liver disorders.

Palmitic/oleic acid-treated HepG2, HSC-LX2 cells, LPS-stimulated RAW264.7, HHSECs, and TGF-β-activated HSC-LX2 cells were used to evaluate the therapeutic potential of vistusertib across liver disease models (n = 3). In vivo efficacy against inflammation, fibrosis, and HCC was assessed using streptozotocin (insulin resistance) and high-fat diet-induced (STAM) MASH models (n = 6), with molecular analyses of oxidative stress, fibrotic, and oncogenic markers confirming broad hepatoprotective activity.

Vistusertib significantly (p < 0.001) reduced lipid accumulation, LPS-driven inflammation, and TGFβ-induced fibrosis in various in vitro models. It also suppressed cell migration (HepG2), sphere formation, and expression of cancer stem cell markers at low concentrations. In the STAM mouse model (C57BL/6 with streptozotocin and high-fat diet), vistusertib significantly (p < 0.05) decreased hepatic lipid accumulation, de novo lipogenesis, and hepatocellular ballooning. MASH-induced fibrotic markers and collagen deposition were markedly attenuated via mTOR signalling modulation. Importantly, vistusertib reduced tumour nodule formation, suggesting its ability to block MASH progression to HCC, with a confirmed favourable safety profile.

Our findings identify vistusertib as a promising candidate for MASH, capable of mitigating disease progression and preventing MASH-to-HCC transition, highlighting its potential in managing metabolic liver disorders.