In hepatocellular carcinoma, the interactions among SPP1, ADAMTS5 and ZBP1 are complex and may synergize in multiple mechanisms.ADAMTS5 and SPP1 may interact in regulating immune cell infiltration in the tumor microenvironment, and ADAMTS5, by degrading the ECM (Mead and Apte, 2018), may enhance the role of SPP1 in the tumor microenvironment.ZBP1, by inducing necrotic apoptosis, may promote local inflammatory responses within tumors (Zheng and Kanneganti, 2020), which together with SPP1 and ADAMTS5 drive tumor progression. This evidence concerns the gene ZBP1 and hepatocellular carcinoma.