Summary Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, and the fastest rising cancer mortality in the U.S. Due to the limited efficacy of existing therapies for established HCC tumors, prognosis for patients remains poor, with five-year survival under 15%. Thus, HCC chemoprevention in cirrhosis is likely the most impactful strategy to improve survival. However, despite the candidate chemopreventive agents suggested in experimental studies, it remains an unmet need due to logistical difficulty in conducting clinical trials that require large sample size and long follow-up time. To overcome the challenge, we identified Prognostic Liver Secretome signature (PLSec) to quantitatively monitor therapeutic modulation of HCC risk level in cirrhosis patients, and predict reduction of future incident HCC. PLSec has been used as a surrogate endpoint in our ongoing and planned HCC chemoprevention clinical trials. Experimental studies in rodent models by us and others suggested that epigallocatechin gallate (EGCG), a green tea catechin, prevents HCC development without any adverse events. Our ex vivo organotypic culture of precision-cut liver slice (PCLS) from cirrhosis patients revealed suppression of high-risk signature by EGCG, supporting its clinical relevance. Based on these promising findings, the goal of our proposal is to test our hypothesis that EGCG treatment safely suppresses PLSec in patients with cirrhosis. Aim 1. Evaluate safety and efficacy of EGCG in cirrhosis patients (phase II double-blinded placebo-controlled clinical trial). We will evaluate 24-week EGCG treatment or placebo in 60 patients (1:1 randomization) with early-stage cirrhosis enriched for elevated HCC risk by a clinical variable-based score (FIB-4 index) and PLSec. Participants will be monitored monthly for adverse events. Serum samples will be obtained before, during, and at the end of treatment. Primary endpoint: reduction of risk level as measured by PLSec (delta-PLSec). Secondary endpoints: safety profile, change in quality of life. Exploratory endpoints: change in on-treatment PLSec, immunohistochemistry of HCC-risk-related markers for participants consented for liver biopsy, and incident HCC. Aim 2. Identify factors associated with response to EGCG in cirrhosis patients. We will evaluate pre-treatment PLSec and clinico-histological variables; on-treatment PLSec modulation and plasma concentration of EGCG and its metabolites for their association with the primary endpoint. We will also assess modulation of the FIB-4 index and liver stiffness measurement by acoustic elastography as potential alternative clinical endpoints to monitor effect of EGCG, We expect to establish novel HCC chemoprevention with a dietary supplement for subsequent pivotal phase III clinical trial toward clinical translation of this approach, which will contribute to a transformative improvement in the outcome of patients with HCC by enabling individual- risk-base...