**4. Molecular typing based on proteome**

Proteins are the direct executors of life activities and proteomics is one of the effective methods to search for molecular markers. The molecular characteristics of 110 cases of early hepatocellular carcinoma were analyzed and compared by proteomics [27]. The heterogeneity of early hepatocellular carcinoma was divided into the subtypes S-I, S-II, and S-III, each of which has a different clinical outcome. TGF-β and other tumor proliferation-related proteins were highly expressed in the S-III subtype, which was consistent with the Hoshida S1 subtype, and the prognosis was poor. S-II and S-I subtypes were characterized by high expression of Wnt and CTNNB1, consistent with Hoshida S2 and S3 subtypes. Proteomics is also an effective way to find drug targets. At present, the direct targets of liver cancer-targeted drugs with multi-kinase inhibitors and immunotherapy with immune checkpoint inhibitors are all proteins. S-III, which is characterized by disrupted cholesterol homeostasis, is associated with the lowest overall rate of survival and the greatest risk of a poor prognosis after first-line surgery. The knockdown of sterol O-acyltransferase 1 (SOAT1)-high expression of which is a signature specific to the S-III subtype-alters the distribution of cellular cholesterol, and effectively suppresses the proliferation and migration of hepatocellular carcinoma. Finally, on the basis of a patient-derived tumor xenograft mouse model of hepatocellular carcinoma, that treatment with avasimibe, an inhibitor of SOAT1, markedly reduced the size of tumors that had high levels of SOAT1 expression, which indicates that SOATI may become a new target of S-III subtype, namely Hoshida S1 subtype liver cancer [27]. Gene mutation induced by aristolochic acid is a characteristic pathogenic factor in China and even in Asia except for viral hepatitis B [28]. The mutation "fingerprint" of aristolochic acid is significantly positively correlated with tumor mutation burden, tumor neoantigen burden, CD8+ T cell infiltration, and immune microenvironment tolerance, suggesting these patients may benefit from immunotherapy [18]. On the other hand, the microenvironment of CTNNB1 mutation patients is immuno-privileged and may not benefit from immunotherapy. Further multi-omics analysis of liver cancer found that CTNNB1 mutation is related to the phosphorylation of serine 36 in ALDOA (fructose-1,6-bisphosphate aldolase) [29]. ALDOA phosphorylation promotes tumor cell proliferation by promoting anaerobic glycolysis and knocking *Research Frontier of Accurate Diagnosis and Treatment Guided by Molecular Typing… DOI: http://dx.doi.org/10.5772/intechopen.99836*

down ALDOA significantly inhibits tumor proliferation. Therefore, ALDOA may be an important potential therapeutic target for CTNNB1 mutant liver cancer.
