Accumulation of Lipid Droplets as an Underlying Cause of the Progression of Fatty Liver Disease to Liver Cancer

NCT07775716 | Active Not Recruiting

• 1 other identifier: PRECURSOR-HCC
• Study Type: interventional
• Target: 35,500
• Locations: 1 country
• Sites: 1

Brief Summary

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the leading cause of chronic liver disease, accounting for an increasing burden of cirrhosis, hepatocellular carcinoma (HCC), and related mortality, thus representing a major emerging public health threat. Currently, the primary unmet clinical needs in progressive MASLD remain the development of non-invasive biomarkers and effective therapeutic options. The objective is to delineate the pathogenic mechanisms driving the transition from hepatic lipid accumulation to steatohepatitis, fibrosis, and HCC, based on the hypothesis that alterations in lipid droplet (LD) biology within hepatocytes and resident liver cells are early, decisive factors in disease progression. To test this, human genetic studies from well-characterized cohorts will be combined with human liver organoids (HLOs) and artificial intelligence (AI) tools. Specifically, common and rare genetic variants will be integrated into partitioned polygenic risk scores (pPRS) to link genetic predisposition to specific LD morphological and functional traits. Furthermore, an innovative high-throughput screening platform using multi-omic approaches will be developed to deconvolve the genetic diversity of MASLD through LD profiling. Finally, these data will be integrated via AI algorithms to refine risk stratification, develop new diagnostic and prognostic tools for cirrhosis and HCC, and identify novel therapeutic targets. Ultimately, the identification of high-risk MASLD subtypes through specific LD pathways will enable precision medicine strategies, significantly improving clinical management.

Conditions

HCC; MASLD

Outcome Measures

Primary Outcomes (2)

• Incidence of High-Risk MASLD with Advanced Liver Fibrosis

  Presence of significant to advanced liver fibrosis, defined as histological or non-invasive stage \>= F2 (evaluated via transient elastography/FibroScan liver stiffness \>7.9 kPa, liver biopsy, or validated non-invasive scoring systems such as NAFLD Fibrosis Score, APRI, or FIB-4). The predictive accuracy of multi-level polygenic risk scores (PRS/pPRS) and multi-omic models in stratifying this risk will be evaluated using area under the receiver operating characteristic curve (AUC-ROC) and logistic regression odds ratios.

  up to 24 months

• Incidence of Hepatocellular Carcinoma (HCC)

  Diagnosis of new or existing Hepatocellular Carcinoma (HCC) confirmed according to AASLD/EASL guidelines using dynamic imaging (Contrast-Enhanced Computed Tomography \[CT\] or Magnetic Resonance Imaging \[MRI\]) or histological examination. The performance of genetic (PRS/pPRS) and multi-omic predictive algorithms in identifying individuals at high risk for developing HCC within the MASLD population will be assessed.

  up to 24 months

Secondary Outcomes (3)

• Comparative Predictive Performance of Partitioned Polygenic Risk Scores (PRS)

  up to 24 months

• Characterization of Subtypes of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

  up to 24 months

• Immunological Profiling and Biomarkers of MASLD Progression

  up to 24 months

Study Arms (1)

A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD

EXPERIMENTAL

The study protocol involves a series of procedural interventions aimed at identifying biomarkers and therapeutic targets for MASLD progression. This includes the collection and processing of liver tissue for the generation of Human Liver Organoids (HLOs), which serve as a primary biological model for testing disease mechanisms. Procedural assessment is further enhanced by the use of HistoIndex digital pathology, a specialized diagnostic device that employs second-harmonic generation (SHG) microscopy for AI-driven, stain-free phenotyping of liver fibrosis and lipid droplet morphology. Additionally, the integration of multi-omic screening platforms constitutes a core technical intervention to deconvolve genetic diversity. These diagnostic and technological interventions are applied alongside standardized clinical monitoring of cohorts (Liver-BIBLE, SERENA, REVEAL, REASON, and FOGS) to correlate molecular data with clinical outcomes such as cirrhosis and HCC development.

Other: Comprehensive Genomic and Transcriptomic Profiling; Other: Patient-Derived Human Liver Organoid (HLO) Development; Other: AI-Driven Digital Pathology (HistoIndex); Other: Targeted LD Lipidomics; Other: AI-Integrated Predictive Risk Modeling

Interventions

Comprehensive Genomic and Transcriptomic Profiling OTHER

DNA isolation followed by Whole Exome Sequencing (WES) to identify rare and common genetic variants. This intervention includes single-cell transcriptomics for precise immunophenotyping of liver resident cells and the mapping of cellular heterogeneity across the MASLD spectrum.

A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD

Patient-Derived Human Liver Organoid (HLO) Development OTHER

Generation and analysis of 3D Human Liver Organoids (HLOs) from patient biological samples. These models are utilized to study lipid droplet (LD) biology, hepatocyte function, and the mechanisms of disease progression in a controlled, patient-specific environment.

A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD

AI-Driven Digital Pathology (HistoIndex) OTHER

Use of a non-invasive, stain-free imaging system based on second-harmonic generation (SHG) microscopy. This device provides automated, AI-driven quantification of liver fibrosis and detailed morphological assessment of lipid droplets.

A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD

Targeted LD Lipidomics OTHER

Advanced lipidomic profiling of lipid droplets (LD) conducted on liver samples to identify specific lipid signatures associated with the transition from simple steatosis to hepatocellular carcinoma (HCC).

A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD

AI-Integrated Predictive Risk Modeling OTHER

Application of artificial intelligence algorithms to integrate multi-omic data (genomic, transcriptomic, lipidomic) with clinical outcomes. This intervention focuses on developing refined risk stratification tools and identifying novel therapeutic targets for cirrhosis and HCC.

A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The retrospective cohort consists of patients previously enrolled in the SERENA, REASON, REVEAL, FOGS, and LIVER BIBLE studies who have provided informed consent for the use of their data.
• High-risk profiles, such as those with a family history of HCC or specific genetic variants (PNPLA3, TM6SF2, MBOAT7), are also included.
• The REASON and REVEAL studies contribute adult patients (≥18 years) who underwent liver biopsies for suspected NASH, liver resections for HCC or other lesions, or whole liver explants.
• The FOGS study includes individuals aged 14-80 who specifically do not present with MASLD, MetALD, or cryptogenic SLD.
• The LIVER BIBLE study provides a control group of blood donors (40-65 years) who are overweight or obese and present at least two metabolic risk factors such as hypertension, dyslipidemia, or impaired fasting glucose.
• The prospective cohort is divided into two distinct groups: a healthy control population and a MASLD/HCC population. Healthy controls must be at least 18 years old with no clinical or imaging evidence of liver disease, no significant metabolic disorders (such as diabetes or severe obesity with BMI \>30), and normal liver function tests. Their alcohol consumption must remain below 20g/day for women and 30g/day for men. The MASLD/HCC population includes adults with a confirmed diagnosis of MASLD or MetALD via imaging or histology. This group encompasses the full spectrum of the disease, from simple steatosis to advanced fibrosis, cirrhosis, and HCC. HCC cases must be diagnosed according to AASLD/EASL guidelines and staged using the BCLC system.
• All prospective participants must provide signed informed consent and have comprehensive clinical and laboratory data available.

You may not qualify if:

• The Retrospective, patients with an alcohol intake exceeding 60/40 g/day (M/F) or those with diagnosed genetic liver conditions-such as hereditary hemochromatosis, Wilson's disease, or Alpha-1 Antitrypsin deficiency-are excluded due to their increased baseline risk for HCC. Additionally, the use of medications known to induce secondary steatosis is a disqualifying factor.

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead

Study Sites (1)

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica

Milan, Milano, 20122, Italy

Location

MeSH Terms

Interventions

Growth and Development

Intervention Hierarchy (Ancestors)

Physiological Phenomena

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator, Medical Doctor

Study Record Dates

• First Submitted: February 2, 2026
• First Posted: August 20, 2026
• Study Start: January 29, 2026
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2028
• Last Updated: August 20, 2026

Record last verified: 2026-04

Locations

IT (1)