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Hepatocyte-Targeted Lipid Nanoparticle Delivery of HERC2 Plasmid Controls Drug-Induced Hepatotoxicity by Limiting
Yunzhi Liu1,2,3, Qishan Xu1,4, Yan Liu1
1Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, 510515, China.
Abstract:
Understanding the molecular mechanisms that bridge hepatic inflammation and liver injury is crucial for developing effective therapeutic strategies for drug-induced liver injury (DILI) management. HECT domain and RCC1-like domain 2 (HERC2) belongs to the large Herc family of ubiquitin E3 ligases, which are implicated in tissue development and inflammation. The observation reveals a pronounced HERC2 expression in specific hepatocyte subsets that proliferate in response to DILI in humans, prompting an investigation into the role of HERC2 in distinct DILI progression. Under the APAP challenge, liver-specific HERC2-deficient mice suffer more severe liver damage. Integrated single-cell RNA sequencing analysis unveils a negative correlation between HERC2 and CYP2E1, a vital metabolic enzyme for xenobiotics, in hepatocytes from APAP-challenged mice. Mechanistically, HERC2 interacts with β-catenin to promote its ubiquitination, thereby governing CYP2E1 transcriptional regulation. Targeted hepatic delivery of lipid nanoparticle-encapsulated HERC2-overexpressing plasmid markedly reduces liver damage caused by APAP overdose. Collectively, these findings elucidate a previously unrecognized protective role of HERC2 in protecting against acute liver injury associated with drug metabolism disorders, highlighting its potential as a therapeutic target in treating DILI.
Insights
HECT domain and RCC1-like domain 2 (HERC2) protects against drug-induced liver injury (DILI) by regulating CYP2E1 metabolism. HERC2 deficiency exacerbates liver damage, while its overexpression offers therapeutic potential for DILI.
Area of Science:
- Biochemistry
- Hepatology
- Molecular Biology
Background:
- Drug-induced liver injury (DILI) poses a significant clinical challenge, necessitating a deeper understanding of its underlying molecular mechanisms.
- HECT domain and RCC1-like domain 2 (HERC2), a ubiquitin E3 ligase, is implicated in inflammation and tissue development.
- Increased HERC2 expression is observed in proliferating hepatocytes during DILI in humans, suggesting a potential role in disease progression.
Purpose of the Study:
- To investigate the role of HERC2 in the pathogenesis and progression of drug-induced liver injury (DILI).
- To elucidate the molecular mechanisms by which HERC2 influences liver response to drug insults.
- To evaluate the therapeutic potential of HERC2 modulation in DILI management.
Main Methods:
- Utilized liver-specific HERC2-deficient mouse models subjected to acetaminophen (APAP) challenge.
- Performed integrated single-cell RNA sequencing analysis on hepatocytes from APAP-treated mice.
- Investigated the interaction between HERC2 and β-catenin, and its effect on CYP2E1 expression.
- Employed targeted hepatic delivery of HERC2-overexpressing plasmids via lipid nanoparticles.
Main Results:
- Liver-specific HERC2 deficiency exacerbated APAP-induced liver injury, indicating a protective role for HERC2.
- Single-cell RNA sequencing revealed a negative correlation between HERC2 and CYP2E1 expression in hepatocytes.
- HERC2 was found to interact with β-catenin, promoting its ubiquitination and regulating CYP2E1 transcription.
- Hepatic delivery of HERC2-overexpressing plasmids significantly attenuated APAP-induced liver damage.
Conclusions:
- HERC2 plays a crucial protective role in mitigating acute liver injury associated with drug metabolism.
- The mechanism involves HERC2-mediated regulation of CYP2E1 via the β-catenin pathway.
- HERC2 represents a promising therapeutic target for managing DILI, particularly that arising from metabolic dysregulation.
