HACD3 promotes the malignant progression of NSCLC by weakening the scaffold between MMK7 and MAPK10

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. Methods: The study assesses the expression of HACD3 in non-small cell lung cancer (NSCLC) patient samples. Additionally, the effects of HACD3 knockdown and overexpression have been explored on in vitro cell proliferation, colony formation, invasion, migration, and cell cycle progression in lung cancer cells, along with in vivo tumorigenesis inside NSG mice. Furthermore, the current study successfully developed a lung cancer model using HACD3 systemic knockout mice formed using Urethan. Transcriptomics helped identify the target of HACD3 promoting NSCLC progression, followed by validation using different experiments. A truncated plasmid and peptide segment of HACD3 was constructed, followed by screening the specific segment promoting lung cancer progression. Results: The results demonstrate that HACD3 is highly expressed in cancer tissues and cells while promoting the malignant progression of NSCLC cells. Downregulating HACD3 activates the MAPK pathway in cancer cells. The specific HACD3 fragment promoting cancer progression is located at aa231-259. Conclusions: The above results indicate that the fatty acid dehydratase HACD3 promotes the malignant progression of lung cancer by suppressing the MAPK pathway. Thus, targeting HACD3 could be a new approach to treating lung cancer.