Work

HACD3 promotes malignant progression of NSCLC by suppressing the MKK7/MAPK10 signaling axis

Year: 2025

Type: article

Abstract: BACKGROUND: HACD3 is from the very long-chain fatty acid dehydratase family and exhibits only mild activity while producing long-chain fatty acids. Numerous studies have uncovered an association of HACD3 with the advancement of diverse cancers. The current study attempts to delve into the potential role of HACD3 in initiating and enhancing lung cancer. OBJECTIVE: This project aims to investigate the role of HACD3 in the malignant progression of lung cancer and its related mechanisms. METHODS: ) mice were generated, assessed for fatty acid profiles (GC-MS), and utilized in a urethane-induced lung cancer model. Transcriptomics and Co-Immunoprecipitation (Co-IP) were used to identify and validate HACD3 interacting partners and downstream pathways. Functional domains were mapped using truncated plasmids and synthetic peptides. RESULTS: HACD3 was found significantly overexpressed in NSCLC tissues and cells. Increased HACD3 levels promoted key malignant behaviors including proliferation and migration in vitro, and accelerated tumor growth in vivo. Genetic deletion of Hacd3 markedly reduced lung tumor formation in a urethane model, an effect independent of major changes to fatty acid metabolism. Mechanistic studies revealed that HACD3 suppresses the MAPK pathway via direct physical interaction with MKK7 and MAPK10. Finally, the core pro-tumorigenic activity was mapped to a specific C-terminal domain encompassing amino acids 231-259. CONCLUSIONS: HACD3 promotes the malignant progression of NSCLC by interacting with MKK7 and MAPK10 to suppress MAPK signaling, independent of its canonical dehydratase activity. The identification of a critical pro-oncogenic domain (aa231-259) suggests that targeting HACD3, potentially via this region, represents a novel therapeutic strategy for NSCLC.

Source: BMC Cancer

DOI: 10.1186/s12885-025-14621-y

Authors: Xiaoying Wang, Huijun Liang, Qindan Du, Ying Li, Yong Zhao

Institutions: Jiangnan University, Wuxi Fourth People's Hospital

Language: English

Topic: Cancer, Lipids, and Metabolism

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,390