Lactylation‐Driven HECTD2 Limits the Response of Hepatocellular Carcinoma to Lenvatinib

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

Abstract Drug resistance remains a major hurdle for the therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, underlying mechanisms remain largely undetermined. Unbiased proteomic screening is performed to identify potential regulators HCC. Patient‐derived organoids, patient‐derived xenograft mouse models, and DEN/CCl 4 induced HCC models are constructed evaluate effects HECTD2 both vitro vivo. found be highly expressed lenvatinib‐resistant cell lines, patient tissues, organoids xenografts. In vivo experiments demonstrated that overexpression limits response treatment. Mechanistically, functions as an E3 ubiquitin ligase KEAP1, which contributes degradation KEAP1 protein. Subsequently, KEAP1/NRF2 signaling pathway initiates antioxidative cells. Lactylation histone 3 on lysine residue 18 facilitates transcription HECTD2. Notably, PLGA‐PEG nanoparticle‐based drug delivery system synthesized, effectively targeting The NPs achieved tumor‐targeting, controlled‐release, biocompatibility, making them promising strategy mitigating resistance. This study identifies nanotherapeutic target overcoming resistance, providing theoretical basis translational application

Language: Английский

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Bridging epigenomics and tumor immunometabolism: molecular mechanisms and therapeutic implications

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: March 8, 2025

Epigenomic modifications—such as DNA methylation, histone acetylation, and methylation—and their implications in tumorigenesis, progression, treatment have emerged a pivotal field cancer research. Tumors undergo metabolic reprogramming to sustain proliferation metastasis nutrient-deficient conditions, while suppressing anti-tumor immunity the tumor microenvironment (TME). Concurrently, immune cells within immunosuppressive TME adaptations, leading alterations function. The complicated interplay between metabolites epigenomic modulation has spotlighted significance of regulation immunometabolism. In this review, characteristics modification associated with tumors are systematically summarized alongside regulatory roles Classical emerging approaches delineated broaden boundaries research on crosstalk immunometabolism epigenomics. Furthermore, we discuss potential therapeutic strategies that target modulate modifications, highlighting burgeoning synergy therapies immunotherapy promising avenue for treatment.

Language: Английский

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Design, Synthesis and Biological Activity Study of γ-Aminobutyric Acid (GABA) Derivatives Containing Bridged Bicyclic Skeletons as BCAT1 Inhibitors

Molecules, Journal Year: 2025, Volume and Issue: 30(4), P. 904 - 904

Published: Feb. 15, 2025

Branched-chain amino acid aminotransferases (BCATs), existing as the two isoforms BCAT1 and BCAT2, are responsible for catabolism of branched-chain acids (BCAAs) highly upregulated implicated in a diverse range cancers. inhibitors represent potential class therapeutic agents cancers; however, none have yet progressed to clinical development. Our earlier research identified WQQ-345 novel inhibitor featuring unique bridged bicyclic skeleton demonstrating both vitro vivo antitumor activity against tyrosine kinase (TKI)-resistant lung cancer with high expression. In present study, we proceeded modify structure by two-round structure-activity relationship (SAR) exploration, leading discovery bicyclo[3.2.1]octene-bearing GABA derivative 7. Compound 7 exhibited 6-fold enhancement enzymatic inhibitory compared parent compound could effectively suppress growth 67R cells that expressed was resistant third-generation TKIs. derivatives an important chemical inhibitors, therefore, findings study great progress potent new structures treatment resistance.

Language: Английский

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Multiple roles of branched-chain amino acid metabolism in tumour progression

Journal of Biomedical Science, Journal Year: 2025, Volume and Issue: 32(1)

Published: April 9, 2025

Abstract Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt the ever-changing microenvironment. Branched-chain amino acids (BCAAs) metabolites are involved in intracellular protein synthesis catabolism, signal transduction, epigenetic modifications, maintenance of oxidative homeostasis. Alterations BCAA metabolism can influence progression various tumours. However, how is dysregulated differs among depending on type; for example, it manifest as decreased leading accumulation, or enhanced uptake increased catabolism. In this review, we describe role different As well discuss metabolic drives therapy resistance evasion antitumour immune response, these pro-cancer effects achieved part by activating mTORC signalling pathway. In-depth investigations into potential mechanisms which affects tumorigenesis enhance our understanding relationship between cancer provide new strategies therapy.

Language: Английский

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Research advances in branched-chain amino acid metabolism in tumors

Molecular and Cellular Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Language: Английский

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