Hepatocellular carcinoma (HCC) prognosis remains dismal due to frequent diagnosis at late, non-curable stages. To improve early tumor detection, practice guidelines recommend semi-annual HCC screening in cirrhosis patients. However, the vast size of the cirrhosis population and the sharp rise of metabolic liver disease, i.e., non-alcoholic fatty liver disease (NAFLD) and newly proposed metabolic dysregulation- associated fatty liver disease (MAFLD) as the new dominant HCC etiology, poses a significant challenge in applying the guideline-recommended HCC screening to the entire target population. Thus, there is an urgent unmet need for biomarkers to predict future HCC risk to identify a subset of NAFLD/MAFLD patients who most need regular HCC screening and enable rational allocation of limited medical resources for the screening. Our previous simulation analysis showed that individual-risk-based personalized HCC screening is significantly more cost-effective than the current “one-size-fits-all” screening strategy. We previously developed a serum-protein-based etiology-agnostic Prognostic Liver Secretome signature (PLSec) to predict long-term HCC risk in general cirrhosis population, which is currently undergoing validation in prospectively collected national (NCI Early Detection Research Network [EDRN] Hepatocellular carcinoma Early Detection Strategy [HEDS]) and state-wide (Texas HCC Consortium [THCCC]) prospective cohorts with NCI support (R01CA222900, U01CA230694). PLSec is also incorporated as an endpoint in ongoing and planned HCC chemoprevention clinical trials to monitor therapeutic modulation of HCC risk level (NCT02273362, NCT04172779, NCT05028829). More recently, we have developed another serum-based biomarker specialized for NAFLD patients (PLSec-NAFLD) as an etiology-specific HCC risk biomarker with ongoing NCI support (R01CA233794) to further improve the PLSec-based HCC risk prediction in metabolic liver disease patients. Our preliminary data indeed suggest that combination of the etiology-agnostic (PLSec) and etiology-specific (PLSec-NAFLD) biomarkers, namely etiology-specific PLSec-NAFLD (etPLSec-NAFLD), improve HCC risk prediction in patients with metabolic liver disease, and also serve as companion biomarkers in HCC chemoprevention trial in metabolic liver disease patients. In this project, we will validate PLSec-NAFLD and etPLSec-NAFLD already available at our CLIA-certified UT Southwestern BioCenter to establish the biomarkers for future clinical trials and studies via the following Specific Aims: Aim 1. Validate the PLSec-NAFLD and etPLSec-NAFLD in NAFLD cirrhosis patients from the EDRN HEDS cohort. Aim 2. Validate the PLSec-NAFLD and etPLSec-NAFLD in MAFLD cirrhosis patients from the THCCC cohort. Aim 3. Evaluate therapeutic modulation of the PLSec-NAFLD in MAFLD cirrhosis patients.