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Background Acetaminophen (APAP)-induced acute liver injury (AILI) is a major form of drug-induced liver injury in which hepatocyte death is shaped not only by intrinsic cellular stress but also by immune-mediated metabolic remodeling. Although myeloid cell metabolic reprogramming has emerged as an important regulator of liver injury, its role in controlling hepatocyte PANoptosis remains unclear. This study aimed to determine whether myeloid Mas exerts a protective role in AILI by regulating lactate-dependent communication between myeloid cells and hepatocytes and thereby modulating PANoptosis.Methods This study generated myeloid-specific Mas-deficient mice and performed single-cell transcriptomic analysis to characterize the cell-specific expression pattern of Mas in AILI. Molecular docking and chromatin immunoprecipitation assays were employed to explore the downstream mechanisms linking myeloid Mas to metabolic regulation and PANoptosis. Co-culture and serum metabolite measurement were further used to assess lactate-mediated intercellular communication and its clinical relevance.Results Mas expression was significantly increased in liver tissues from patients with AILI and in APAP-treated mice, with single-cell transcriptomic analysis showing predominant enrichment of Mas in myeloid cells. Myeloid-specific Mas deletion markedly exacerbated AILI, accompanied by enhanced HIF-1α–PKM2-driven glycolysis and excessive lactate production in myeloid cells. Excessive lactate acted as a critical metabolite that promoted DDIT3 lactylation and nuclear translocation in hepatocytes, leading to transcriptional upregulation of ZBP1 and subsequent PANoptosis. These results were consistently validated by complementary in vivo and in vitro experiments. In addition, serum lactate levels were significantly elevated in patients with AILI, indicating its potential clinical value as a biomarker.Conclusions Myeloid Mas exerts a protective effect in AILI by restraining HIF-1α–PKM2-driven metabolic reprogramming and lactate production, thereby preventing DDIT3 lactylation-dependent nuclear translocation, ZBP1 transcriptional activation, and subsequent hepatocyte PANoptosis. These findings reveal that immune metabolic reprogramming can dictate parenchymal cell death programs through intercellular communication and identify myeloid Mas as a potential therapeutic target in acute liver injury.