Abstract 3601: Elevated short-chain fatty acid level and increased risk of hepatocellular carcinoma in a prospective cohort study

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Background: Hepatocellular carcinoma (HCC) makes up 80-90% of primary liver cancers and is typically detected at an advanced stage because of its silent nature of progression and a lack of effective non-invasive early detection biomarkers. Gut-derived metabolites such as short-chain fatty acids (SCFAs) play a key role in liver health and may impact the progression of early non-malignant stages of liver disease to malignant transformation to HCC. Although most of studies have shown that SCFAs including acetate, butyrate, and propionate have been associated with lower risk of intestinal disease, some experimental studies have shown dysregulated metabolism of SCFAs may induce proinflammatory milieu for liver disease progress. The goal of this study is to investigate whether metabolomic profiling of SCFAs in baseline serum is associated with risk of HCC development. Methods: We performed a nested case-control study with 100 incident HCC cases and 100 individually matched healthy controls within the Singapore Chinese Health Study, a cohort of 63,257 men and women aged 45-74 years at enrollment in 1993-1998. The incidence of HCC among cohort participants was annually surveilled using the nationwide Singapore Cancer Registry. Serum acetic, butyric, propionic, and valeric acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays. The conditional logistic regression was used to evaluate the association between SCFAs and HCC risk using odds ratios (ORs) and their 95% confidence intervals (CI). Results: Cases and controls were comparable in distributions by age, body mass index (BMI), alcohol consumption and smoking status. Individuals with HCC were more likely to be HBsAg positive and had a history of diabetes than controls. Among controls, the summed all SCFAs and total butyric acid and its metabolites were positively associated with BMI (P trend < 0.05). The summed and most of individual SCFAs measured were significantly elevated in HCC compared with controls. Compared to the lowest tertile, the OR (95% CI) of HCC for the highest tertile of summed all SCFAs and total butyric acids was 3.24 (1.45-7.24) and 2.78 (1.27-6.12) after adjusting for age, sex, BMI, alcohol consumption, smoking status, type 2 diabetes, and HBsAg status (both P’s for trend < 0.01). Conclusion: The present analysis demonstrated a statistically significant association between elevated SCFA levels and increased risk of HCC in a prospective cohort of Singaporean Chinese. These results align with increased risk of HCC within this cohort with elevations in other metabolites such as bile acids. Mapping metabolic profile changes in liver disease progression to cancer will provide clinicians with a novel biomarker for risk stratification and early detection. Citation Format: Sindhu Karnam, Wei Jia, Renwei Wang, Jennifer Adams-Haduch, Woon-Puay Koh, Jian-Min Yuan. Elevated short-chain fatty acid level and increased risk of hepatocellular carcinoma in a prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3601.