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Published on: January 20, 2023
Elevated HSP70 Ameliorates Liver Failure Patients via Its Novel Natural Inhibitor
Yu Zhang1, Lina Jiang1, Yiyun Jiang1
1Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
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 (IC50 = 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.
Insights
Heat shock protein 70 (HSP70) is elevated in liver failure, exacerbating injury and predicting poor outcomes. A natural inhibitor, aPPD, significantly reduced liver damage and mortality, highlighting HSP70 as a therapeutic target.
Area of Science:
- Hepatology and immunology
- Molecular biology
- Biomarker discovery
Background:
- Liver failure results from severe hepatocyte injury, lacking effective biomarkers and treatments.
- Heat shock protein 70 (HSP70) is involved in cellular stress and inflammation, but its specific role in liver failure is not well understood.
Purpose of the Study:
- To elucidate the mechanistic role of HSP70 in liver failure.
- To evaluate HSP70 as a potential therapeutic target for liver failure.
Main Methods:
- Analysis of HSP70 levels in liver failure patients and correlation with clinical outcomes.
- Investigation of HSP70's biological function using a GalN/LPS-induced mouse model of liver failure.
- Assessment of therapeutic interventions including HSP70 inhibition and a natural compound, aPPD.
Main Results:
- HSP70 was significantly elevated in liver failure patients and correlated with disease severity markers like ALT and pro-inflammatory cytokines.
- In mice, HSP70 inhibition reduced liver injury, while exogenous HSP70 exacerbated it by promoting inflammation.
- The HSP70 inhibitor blocked TNF-α-induced apoptosis via the NF-κB pathway.
- Ginseng metabolite aPPD inhibited HSP70, significantly reducing liver failure severity and mortality in mice.
Conclusions:
- HSP70 plays a critical immunopathologic role in liver failure, representing a viable therapeutic target.
- The natural HSP70 inhibitor aPPD demonstrates significant protective effects, suggesting its potential as a novel treatment for liver failure.
