Drug development in primary sclerosing cholangitis (PSC) is challenging, giving orphan disease status and variable rates of disease progression. A potential route for new therapies is through attenuation of symptoms. However, the epidemiology of symptomatic presentations and how they inherently fluctuate over time is not known. We conducted a prospective, multicentre study (trial registration: ISRCTN:15518794) to quantify the prevalence, intensity and variability of pruritus in PSC. Participants underwent face-to-face symptom assessment through the itch numerical rating scale (NRS) and 5D-itch tool. Clinical, radiological and biochemical factors associated with pruritus intensity were determined, alongside the impact on health-related quality-of-life (EQ-5D 5L and chronic liver disease questionnaires [CLDQ]) over 12-week intervals (up to 48+/-4 weeks). In all, 220 patients participated, of whom n=116 reported pruritus, with n=56 scoring NRS worst itch ≥4. Median 5D-itch was greater in people with cirrhosis (11.0 vs 8.0), transient elastography readings >8.0kPa (9.5 vs 5.0) and a history of ascending cholangitis (11.0 vs 7.0) (p<0.01; all). 5D-itch correlated positively with serum bilirubin, ALP, ALT and AST; and negatively with CLDQ and EQ-5D 5L. In patients scoring NRS≥4, 61.5% reported persistent pruritus intensity over 48 weeks. Reciprocally, 46.2% experienced a spontaneous ≥2 point reduction in NRS without the addition of a new anti-pruritic agent. One in 4 PSC patients experience moderate-severe pruritus, with greater symptom intensity in those with advanced disease. Our dataset is able to serve as a reference tool to aid future interventional study design, with regards anti-pruritus therapies in PSC.

Approximately 10% of human hepatocellular carcinomas (HCC) exhibit concurrent c-MET activation and β-catenin gain-of-function mutations, representing a clinically relevant HCC subtype. This study aimed to investigate the role of mTORC2/AKT signaling in this subtype and identify potential therapeutic targets. The mTORC2/AKT cascade was activated in c-Met/β-cateninΔ90 HCC lesions. Genetic ablation of Rictor, the essential mTORC2 subunit, strongly suppressed c-Met/β-cateninΔ90-dependent hepatocarcinogenesis. Mechanistically, both the TSC2/mTORC1 axis and FOXO1 transcription factors functioned as critical downstream effectors of mTORC2/AKT in this model. We further identified RNF125 as a direct transcriptional target of FOXO1. RNF125 overexpression significantly inhibited tumorigenesis in the c-Met/β-cateninΔ90 model and suppressed liver cancer cell growth in vitro. Notably, using an in vivo doxycycline-inducible system, we found that inducing RNF125 expression in established c-Met/β-cateninΔ90 HCC suppressed tumor progression, suggesting that activation of RNF125 may have translational implications for HCC treatment. Our study, for the first time, established the mTORC2/AKT/FOXO1/RNF125 axis as a critical driver and therapeutic vulnerability in c-MET-activated/β-catenin-mutated HCC. Our study filled a critical gap by defining the tumor-suppressive role of FOXO1 specifically in this HCC subtype. Furthermore, our results positioned RNF125 as a promising therapeutic target for this aggressive HCC subtype.