HCCNCT07775716

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

A study testing Comprehensive Genomic and Transcriptomic Profiling, Patient-Derived Human Liver Organoid (HLO) Development and AI-Driven Digital Pathology (HistoIndex) in people with HCC and MASLD, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 80 yearsHealthy volunteers can take part
Conditions the study is for: HCC, MASLD
What is being tested?: Comprehensive Genomic and Transcriptomic Profiling, Patient-Derived Human Liver Organoid (HLO) Development and AI-Driven Digital Pathology (HistoIndex)
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 35,500 participants
Where: 1 siteItaly
Study dates: 29 Jan 2026to 31 Dec 2028
Phase: Interventional
Are there results?: Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 80 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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.
In the SERENA study, inclusion is restricted to patients aged 45-75 with a diagnosis of MASLD, MetALD, or cryptogenic SLD, showing evidence of F3-F4 fibrosis or cirrhosis through histology, imaging, or non-invasive markers (stiffness >7.9 kPa).
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.

Who cannot join

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.
The SERENA study, any prior diagnosis of HCC before the study start date or a medical prognosis of less than two years results in exclusion.
Prospective participants are excluded if they present with liver diseases of known etiologies other than MASLD, including viral, autoimmune, or purely alcoholic cirrhosis. Genetic liver diseases associated with high HCC risk (e.g., Wilson's disease, Hemochromatosis) and the presence of non-HCC hepatic malignancies, such as cholangiocarcinoma or secondary metastases, are also grounds for exclusion. Furthermore, patients are ineligible if they suffer from severe concurrent comorbidities-such as advanced renal or heart failure or systemic infections-that could interfere with study compliance or data interpretation. Finally, the ongoing use of steatogenic medications remains a strict exclusion criterion for this cohort.

Trial locations and contacts

1 site in 1 country.

Italy1 site

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica
Milan, Milano, 20122

Other trials in Italy

About this study

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

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Comprehensive Genomic and Transcriptomic ProfilingOther
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.
Patient-Derived Human Liver Organoid (HLO) DevelopmentOther
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.
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.
Targeted LD LipidomicsOther
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).
AI-Integrated Predictive Risk ModelingOther
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.

Study groups in NCT07775716
Study group	Role	What they receive
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. Receives: 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

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: up to 24 months

Secondary outcomes (3)

Comparative Predictive Performance of Partitioned Polygenic Risk Scores (PRS)
Evaluation and comparison of the predictive power among different polygenic risk score constructs (hepatic lipid retention-pPRS, concordant-pPRS, and multi-level polygenic risk scores [mlpPRS]) in predicting the development of liver fibrosis, as measured by the Area Under the Receiver Operating Characteristic curve (AUC-ROC).
Measured: up to 24 months
Characterization of Subtypes of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Differentiation of distinct biological subtypes of MASLD based on lipid droplet (LD) phenotypic features (morphology, lipidomic composition, live-imaging kinetics, and transcriptomic profiling) measured in human liver organoids (HLOs) and liver tissues using confocal microscopy, holotomography, and mass spectrometry.
Measured: up to 24 months
Immunological Profiling and Biomarkers of MASLD Progression
Identification of immune cell phenotypes and inflammatory response patterns associated with disease progression and HCC development, measured by single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) and quantification of serum immune biomarkers across genetic risk strata.
Measured: up to 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

29 Jan 202631 Dec 2028

First posted20 Aug 2026
Study start29 Jan 2026
Primary completion31 Dec 2026 (estimated)
Study completion31 Dec 2028 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for HCCStudies of the same condition, open and under way.
More trials run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Prevention
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrolment: 35,500 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT07775716
Sponsor's protocol ID: PRECURSOR-HCC
Status last verified: Apr 2026
First submitted: 2 Feb 2026
Last updated: 20 Aug 2026
Results posted: No
FDA-regulated drug: No
FDA-regulated device: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All HCC trials

Study at a glance

From the registry record, last updated by the sponsor on 20 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Accumulation of Lipid Droplets as an Underlying Cause of the Progression of Fatty Liver Disease to Liver Cancer
ClinicalTrials.gov ID: NCT07775716
Acronym / sponsor ID: PRECURSOR-HCC
Conditions: HCC, MASLD
Study type: Interventional
Recruitment status: Active, not recruiting
Enrolment: 35,500 participants (estimated)
Lead sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoUniversity, hospital or other
Study start: 29 Jan 2026 (actual)
Primary completion: 31 Dec 2026 (estimated)
Study completion: 31 Dec 2028 (estimated)
First posted: 20 Aug 2026 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Prevention
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD	Experimental	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 ModelingThe 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.

Who may qualify

Ages: 18 to 80 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (8 listed)

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.
In the SERENA study, inclusion is restricted to patients aged 45-75 with a diagnosis of MASLD, MetALD, or cryptogenic SLD, showing evidence of F3-F4 fibrosis or cirrhosis through histology, imaging, or non-invasive markers (stiffness >7.9 kPa).
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.

Key exclusion criteria (3 listed)

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.
The SERENA study, any prior diagnosis of HCC before the study start date or a medical prognosis of less than two years results in exclusion.
Prospective participants are excluded if they present with liver diseases of known etiologies other than MASLD, including viral, autoimmune, or purely alcoholic cirrhosis. Genetic liver diseases associated with high HCC risk (e.g., Wilson's disease, Hemochromatosis) and the presence of non-HCC hepatic malignancies, such as cholangiocarcinoma or secondary metastases, are also grounds for exclusion. Furthermore, patients are ineligible if they suffer from severe concurrent comorbidities-such as advanced renal or heart failure or systemic infections-that could interfere with study compliance or data interpretation. Finally, the ongoing use of steatogenic medications remains a strict exclusion criterion for this cohort.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Comprehensive Genomic and Transcriptomic ProfilingDNA 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.	Other	A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD
Patient-Derived Human Liver Organoid (HLO) DevelopmentGeneration 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.	Other	A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD
AI-Driven Digital Pathology (HistoIndex)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.	Other	A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD
Targeted LD LipidomicsAdvanced 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).	Other	A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD
AI-Integrated Predictive Risk ModelingApplication 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.	Other	A Multicenter Longitudinal Study on the Pathogenetic Drivers of MASLD

Primary outcome

Incidence of High-Risk MASLD with Advanced Liver Fibrosis
Time frame: up to 24 months
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.
Incidence of Hepatocellular Carcinoma (HCC)
Time frame: up to 24 months
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.

3 secondary outcomes

Comparative Predictive Performance of Partitioned Polygenic Risk Scores (PRS)
Time frame: up to 24 months
Characterization of Subtypes of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
Time frame: up to 24 months
Immunological Profiling and Biomarkers of MASLD Progression
Time frame: up to 24 months

Results and safety

This study is still under way. Results are not available in the source record yet.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 20 Aug 2026.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 20 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of High-Risk MASLD with Advanced Liver Fibrosis (time frame: up to 24 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07775716.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Aug 2026.