Elevated HSP70 Ameliorates Liver Failure Patients via Its Novel Natural Inhibitor

ABSTRACT Background Liver failure is a severe consequence of extensive hepatocyte injury and lacks sensitive biomarkers and effective therapies. Heat shock protein 70 (HSP70) is implicated in stress responses and inflammation, but its precise role in liver failure remains unclear. Aims We aimed to determine HSP70's mechanistic role, with dual objectives: delineating its pathophysiological functions and assessing therapeutic potential. Methods Levels of HSP70 in liver failure patients and clinical significance were analyzed. The biological function of HSP70 was investigated in GalN/LPS liver failure mice. Results HSP70 was significantly elevated in 82 liver failure patients (blood: 6.68‐fold, p < 0.001; tissues: p < 0.01) versus healthy controls, correlating with ALT ( r = 0.478, p < 0.001) and proinflammatory cytokines (TNF‐α: r = 0.485, IL‐6: r = 0.383, IFN‐γ: r = 0.227; all p < 0.05). Higher serum HSP70 predicted poorer clinical recovery in Kaplan–Meier analysis. Neutralizing antibody inhibition of circulating HSP70 reduced liver injury in liver failure mice (ALT reduction: 43%, p < 0.05), while exogenous HSP70 worsened it (ALT increase: 2.86‐fold, p < 0.05) via increased macrophage proinflammatory production. Besides, the HSP70 inhibitor blocked TNF‐α‐mediated apoptosis by inhibiting the NF‐κB pathway. Notably, ginseng metabolite 20( S )‐protopanaxadiol (aPPD) was a natural HSP70 inhibitor (IC 50 = 2.85 μM), preventing liver failure severity (ALT reduction: 92%) and reducing mortality by 64%. Conclusions These findings underlined the immunopathologic role of HSP70 and a promising therapeutic target in liver failure. The protective role of aPPD suggested that it might serve as a promising candidate for liver failure treatment.