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Abstract：
Liver resection (LR) is the primary treatment for hepatic tumors, yet posthepatectomy liver failure (PHLF) remains a significant concern. While the precise etiology of PHLF remains elusive, dysregulated inflammatory processes are pivotal. Therefore, we explored the theragnostic potential of extracellular high-mobility-group-box protein 1 (HMGB1), a key damage-associated molecular pattern (DAMP) released by hepatocytes, in liver recovery post LR in patients and animal models. Plasma from 96 LR patients and liver tissues from a subset of 24 LR patients were analyzed for HMGB1 levels, and associations with PHLF and liver injury markers were assessed. In a murine LR model, the HMGB1 inhibitor glycyrrhizin, was administered to assess its impact on liver regeneration. Furthermore, plasma levels of keratin-18 (K18) and cleaved cytokeratin-18 (ccK18) were quantified to assess suitability as predictive biomarkers for PHLF. Patients experiencing PHLF exhibited elevated levels of intrahepatic and circulating HMGB1, correlating with markers of liver injury. In a murine LR model, inhibition of HMGB1 improved liver function, reduced steatosis, enhanced regeneration and decreased hepatic cell death. Elevated levels of hepatic cell death markers K18 and ccK18 were detected in patients with PHLF and correlations with levels of circulating HMGB1 was observed. Our study underscores the therapeutic and predictive potential of HMGB1 in PHLF mitigation. Elevated HMGB1, K18, and ccK18 levels correlate with patient outcomes, highlighting their predictive significance. Targeting HMGB1 enhances liver regeneration in murine LR models, emphasizing its role in potential intervention and prediction strategies for liver surgery.
摘要：
肝切除术（LR）是肝肿瘤的主要治疗方法，然而，切除术后肝功能衰竭（PHLF）仍然是一个重要的问题。虽然PHLF的确切病因仍然难以捉摸，失调的炎症过程至关重要.因此,我们探索了细胞外高迁移率族框蛋白1（HMGB1）的热不可知潜力，肝细胞释放的关键损伤相关分子模式（DAMP），患者和动物模型LR后肝脏恢复。分析96名LR患者的血浆和24名LR患者的肝组织的HMGB1水平，并评估了与PHLF和肝损伤标志物的关联。在鼠LR模型中，HMGB1抑制剂甘草酸，给予评估其对肝再生的影响。此外，对血浆角蛋白-18(K18)和裂解的细胞角蛋白-18(ccK18)水平进行定量,以评估作为PHLF预测生物标志物的适宜性.经历PHLF的患者表现出肝内和循环HMGB1水平升高，与肝损伤标志物相关。在鼠LR模型中，抑制HMGB1改善肝功能，脂肪变性减少,增强再生和减少肝细胞死亡。在PHLF患者中检测到肝细胞死亡标志物K18和ccK18水平升高，并观察其与循环HMGB1水平的相关性。我们的研究强调了HMGB1在PHLF缓解中的治疗和预测潜力。HMGB1、K18和ccK18水平升高与患者预后相关，强调其预测意义。靶向HMGB1增强小鼠LR模型的肝再生，强调其在肝脏手术的潜在干预和预测策略中的作用。
