<p>Alcohol-related liver disease (ALD) is increasingly affecting younger populations globally and has become the leading cause of rising liver-related morbidity and mortality. Chronic alcohol exposure over a long period of time has been shown to result in a continuum of pathological processes including liver inflammation, fibrosis, and hepatocellular carcinoma (HCC). However, the therapeutic options for ALD are still limited due to its multifactorial morbidity mechanisms and treatment resistance. This review focuses on the critical regulatory role of the P2X4-P2X7 purinergic axis in ALD pathogenesis, and elucidates that extracellular ATP (eATP), a damage-associated molecular pattern (DAMP) released from alcohol-injured hepatocytes, activates this axis to drive ALD progression. The interaction between P2X4 and P2X7 receptors, including functional synergy and intracellular signal crosstalk, amplifies inflammatory signaling, promotes hepatic stellate cell (HSC) activation, and fosters an immunosuppressive microenvironment during fibrogenesis, ultimately leading to malignant transformation and impaired immunotherapeutic efficacy. Therefore, targeting the P2X4-P2X7 axis through selective receptor antagonism or combining antifibrotic with immunotherapeutic approaches may be a potential strategy to limit fibrosis and improve immunotherapeutic resistance. By synthesizing recent preclinical evidence, this review summarizes the pathogenic role of the P2X4-P2X7 axis in ALD and discusses the prospects of novel axis-based therapies to address unmet clinical needs in ALD management. Notably, most preclinical studies in this field lack standardized blank/sham control groups, which limits the causal inference of purinergic signaling in ALD progression.</p>