AUTHOR=Foglia Beatrice , Sutti Salvatore , Cannito Stefania , Rosso Chiara , Maggiora Marina , Casalino Alice , Bocca Claudia , Novo Erica , Protopapa Francesca , Ramavath Naresh Naik , Provera Alessia , Gambella Alessandro , Bugianesi Elisabetta , Tacke Frank , Albano Emanuele , Parola Maurizio 

TITLE=Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1342404

DOI=10.3389/fimmu.2024.1342404

ISSN=1664-3224

ABSTRACT=Background. Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), previously Non-Alcoholic Fatty Liver Disease (NAFLD), is a leading cause of chronic liver disease worldwide. In 20-30% of MASLD patients the disease progress to Metabolic dysfunction-Associated SteatoHepatitis (MASH, previously NASH) which can lead to fibrosis/cirrhosis, liver failure as well as hepatocellular carcinoma (HCC). Here we investigated the role of histidine-rich glycoprotein (HRG), a plasma protein produced by hepatocytes, in MASLD/MASH progression and HCC development.Methods. The role of HRG was investigated by morphological, cellular and molecular biology approaches in: a) HRG knock-out mice (HRG -/ -mice) fed on a CDAA dietary protocol or a MASH related diethyl-nitrosamine/CDAA protocol of hepatocarcinogenesis; b) THP1 monocytic cells treated with purified HRG; c) well characterized cohorts of MASLD patients with or without HCC.Results. In non-neoplastic settings murine and clinical data indicate that HRG increase significantly in parallel with disease progression. In particular, in MASLD/MASH patients, higher levels of HRG plasma levels were detected in subject with extensive fibrosis/cirrhosis. When submitted to the procarcinogenic protocol HRG -/-mice showed a significant decrease in the volume and number of HCC nodules in relation to decreased infiltration of macrophages producing pro-inflammatory mediators, including IL-1β, IL-6, IL-12, IL-10 and VEGF as well as impaired angiogenesis. Histopathological analysis (H-score) of MASH-related HCC indicate that the higher HRG positivity in peritumoral tissue significantly correlates with a lower overall patient survival and an increased recurrence. Moreover, a significant increase in HRG plasma levels was detected in cirrhotic (F4) patients and in patients carrying HCC vs F0/F1 patients.Murine and clinical data indicate that HRG, play a significant role in MASLD/MASH progression to HCC by supporting a specific population of tumor-associated macrophages with proinflammatory response and pro-angiogenetic capabilities which critically support cancer cell survival. Furthermore, our data suggest HRG as a possible prognostic predictor in HCC patients with MASLD/MASH-related HCCs.