<p>Acute-on-chronic liver failure (ACLF) is associated with high mortality and multi-organ damage in chronic liver disease. This study investigated the role of CD45⁺ erythroid progenitor cells (EPCs) in ACLF progression and underlying mechanisms. CD45⁺ EPCs from 22 patients with hepatitis B virus-related hepatocellular carcinoma (HCC) were analyzed by flow cytometry. Immunofluorescence was used to visualize cell distribution in liver tissue. Mitochondrial function assays and RNA sequencing were performed on isolated CD45⁺ EPCs. In vitro co-culture of CD45⁺ EPCs with human umbilical vein endothelial cells (HUVECs) was used. ACLF and chronic liver injury mouse models were used to explore pathological mechanisms, and adoptive transfer experiments evaluated survival and organ injury. CD45⁺ EPCs were elevated in the circulation and liver of ACLF mice, and adoptive transfer of these EPCs reduced survival in recipients. Among patients with Barcelona Clinic Liver Cancer Staging stage D HCC, those with decompensated liver function (Child–Pugh grade C) had significantly higher circulating CD45⁺ EPCs than those with compensated function (Child–Pugh grade A). EPCs were predominantly localized near vascular endothelial cells in both patients with ACLF and mouse models. CD45⁺ EPCs from patients displayed mitochondrial retention and ferroptosis. In vitro, ACLF plasma with CD45⁺ EPCs induced HUVEC death via ferroptotic products, primarily malondialdehyde, which activated FAO. CD45⁺ EPCs accumulated in the liver, spleen, and brain and correlated with hepatic and cerebral injury. Pharmacological FAO inhibition improved ACLF mice survival. These findings identify CD45⁺ EPCs as key mediators of ACLF progression via mitochondrial dysfunction and FAO-mediated endothelial injury, highlighting their therapeutic potential.</p>