Background <p>Hepatocellular carcinoma (HCC) is frequently identified at advanced stages. This constrains therapeutic options and results in poor prognosis. P2RX4 is an ATP-gated ion channel that modulates calcium influx. It participates in cellular proliferation, inflammatory processes, and immunological reactions. Nonetheless, its role in HCC remains poorly comprehended. This study explored the expression, function, and immunological effects of P2RX4 in HCC.</p> Methods <p>We examined P2RX4 expression using TCGA-LIHC and TIMER2.0 databases. Protein levels were validated using immunohistochemistry in 140 HCC tissues. A prognostic model was developed utilising P2RX4 expression. In vitro investigations were conducted subsequent to the silencing of P2RX4. The experiments encompassed cell proliferation, invasion, and colony formation. We further conducted transcriptome sequencing. Ion concentrations were quantified with ICP-OES. PI3K/AKT activation was evaluated using Western blotting.</p> Results <p>P2RX4 exhibited elevated expression in HCC tissues. Its expression was associated with advanced tumor stage and poor prognosis. Silencing of P2RX4 decreased tumour cell proliferation and invasion. It also reduced intracellular calcium levels and inhibited AKT phosphorylation. Elevated P2RX4 levels correlated with an increased presence of M0 macrophages and Tregs, a reduced number of monocytes, and a poorer anticipated response to immunotherapy.</p> Conclusions <p>P2RX4 may facilitate HCC progression by augmenting calcium influx, activating the PI3K/AKT pathway, and diminishing anti-tumor immunity. It may function as a biomarker and therapeutic target in HCC. Additional, in vivo investigations are required to validate these findings.</p>