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Lactylation-Driven HECTD2 Limits the Response of Hepatocellular Carcinoma to Lenvatinib
Runyu Dong1,2, Yao Fei2, Yiren He1
1Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
Abstract:
Drug resistance remains a major hurdle for the therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, the underlying mechanisms remain largely undetermined. Unbiased proteomic screening is performed to identify the potential regulators of lenvatinib resistance in HCC. Patient-derived organoids, patient-derived xenograft mouse models, and DEN/CCl4 induced HCC models are constructed to evaluate the effects of HECTD2 both in vitro and in vivo. HECTD2 is found to be highly expressed in lenvatinib-resistant HCC cell lines, patient tissues, and patient-derived organoids and xenografts. In vitro and in vivo experiments demonstrated that overexpression of HECTD2 limits the response of HCC to lenvatinib treatment. Mechanistically, HECTD2 functions as an E3 ubiquitin ligase of KEAP1, which contributes to the degradation of KEAP1 protein. Subsequently, the KEAP1/NRF2 signaling pathway initiates the antioxidative response of HCC cells. Lactylation of histone 3 on lysine residue 18 facilitates the transcription of HECTD2. Notably, a PLGA-PEG nanoparticle-based drug delivery system is synthesized, effectively targeting HECTD2 in vivo. The NPs achieved tumor-targeting, controlled-release, and biocompatibility, making them a promising therapeutic strategy for mitigating lenvatinib resistance. This study identifies HECTD2 as a nanotherapeutic target for overcoming lenvatinib resistance, providing a theoretical basis and translational application for HCC treatment.
Insights
HECTD2 overexpression drives lenvatinib resistance in hepatocellular carcinoma (HCC) by degrading KEAP1 and activating antioxidant pathways. Targeting HECTD2 with nanoparticles offers a promising strategy to overcome this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Drug resistance to lenvatinib significantly limits its effectiveness in treating hepatocellular carcinoma (HCC).
- The molecular mechanisms underlying lenvatinib resistance in HCC are not fully understood.
- Identifying novel therapeutic targets is crucial for improving HCC treatment outcomes.
Purpose of the Study:
- To identify key regulators of lenvatinib resistance in HCC using unbiased proteomic screening.
- To investigate the role of HECTD2 in lenvatinib resistance in vitro and in vivo.
- To develop a targeted nanotherapeutic strategy to overcome lenvatinib resistance in HCC.
Main Methods:
- Unbiased proteomic screening to identify potential regulators.
- Utilized patient-derived organoids, xenograft mouse models, and DEN/CCl4-induced HCC models.
- Investigated HECTD2's mechanism involving KEAP1/NRF2 pathway and histone lactylation.
- Synthesized and evaluated PLGA-PEG nanoparticles for HECTD2 targeting.
Main Results:
- HECTD2 was highly expressed in lenvatinib-resistant HCC cells, tissues, and models.
- HECTD2 overexpression diminished HCC response to lenvatinib.
- HECTD2 acts as an E3 ubiquitin ligase for KEAP1, promoting its degradation and activating the KEAP1/NRF2 antioxidant pathway.
- Histone lactylation at H3K18 facilitates HECTD2 transcription.
- Targeted nanoparticles demonstrated tumor-targeting, controlled release, and biocompatibility.
Conclusions:
- HECTD2 is a critical mediator of lenvatinib resistance in HCC.
- Targeting HECTD2 via nanotherapeutics presents a viable strategy to overcome lenvatinib resistance.
- This study provides a theoretical and translational foundation for novel HCC treatment approaches.
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