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Meihua Mei,1– 4,* Danping Liu,1– 4,* Xiuxin Tang,1– 4,* Ying You,1– 4 Baogang Peng,5 Xiaoshun He,1– 3 Junqi Huang1– 4 1Organ Transplant Center, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Organ Donation & Transplant Immunology, Guangzhou, 510080, People’s Republic of China; 3Guangdong Provincial International Cooperation Base of Science & Technology (Organ Transplantation), Guangzhou, 510080, People’s Republic of China; 4Department of Laboratory Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 5Hepatobiliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junqi Huang, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhong Shan Er Lu, Guangzhou, 510080, People’s Republic of China, Tel +86 (20) 28823388 ext. 8670, Email huangjq@mail.sysu.edu.cnPurpose: To clarify the underlying regulatory mechanisms of progression from liver cirrhosis to hepatocellular carcinoma (HCC), we analyzed the microbiomics, metabolomics, and proteomics in plasma and tissues from patients with HCC or decompensated liver cirrhosis (DC).Patients and Methods: Tissues and plasma from 44 HCC patients and 28 patients with DC were collected for metabolomic analysis. 16S rRNA sequencing was performed in nine HCC tissues (HCCT), four distal noncancerous tissues (HCCN), and 11 DC tissues (DCT). Five HCC tissues had liver cirrhosis (HCCT-LC). Five hepatocellular carcinoma tissues without liver cirrhosis (HCCT-NLC) and five DCT were selected for proteomic sequencing. After combining proteomic and metabolomic analysis, we constructed a mouse model of chronic liver injury using carbon tetrachloride (CCl4) and treated them with vitamin B6 (VB6).Results: 16s rRNA sequence results showed that HCC tissues had higher alpha diversity. The highest LDA scores were detected for Elizabethkingia in HCCT, Subsaxibacter in DCT, and Stenotrophomon in HCCN. Metabolomics results demonstrated some metabolites, including capric acid, L-threonate, choline, alpha-D-Glucose, D-ribose, betaine, 2E-eicosenoic acid, linoleic acid, L-palmitoylcarnitine, taurodeoxycholic acid, L-pyroglutamic acid, androsterone sulfate, and phthalic acid mono-2-ethylhexyl ester (MEHP), had better diagnostic efficacy than AFP (AUC: 0.852; 95% CI: 0.749, 0.954). In a combined analysis of metabolomics and proteomics, we found that HCCT-LC had more obvious disorders of VB6 metabolism and pentose and glucuronate interconversions than DCT, and kynurenine metabolism disorder was more significant in HCCT-LC than in HCCT-NLC. In the CCl4-induced chronic liver injury model, after VB6 supplementation, inflammatory cell infiltration, hepatocyte edema, and degeneration were significantly improved.Conclusion: We found significant differences in the flora distribution between HCCT and DC; MEHP was a new diagnostic biomarker of HCC, and VB6 ameliorated the inflammatory cell infiltration, hepatocyte edema, and degeneration in chronic liver injury.Keywords: hepatocellular carcinoma, cirrhosis, proteomics, metabolomics, microbiomics, vitamin B6