Identification of Central Genes in the Pathogenesis of Lipid Metabolism in Chronic Lymphocytic Leukaemia: A Multi-Omics Study Integrating Machine Learning and Mendelian Randomisation.

ZDHHC8 (ZDHHC Palmitoyltransferase 8) is a key gene that regulates cancer cell proliferation and is a potential therapeutic target. It is linked to a poor prognosis and is markedly overexpressed in many malignancies, including chronic lymphocytic leukemia (CLL). However, its pathogenic mechanism in CLL remains unclear. To identify important genes, RNA sequencing data from the Gene Expression Omnibus (GEO) collection were analyzed for differential expression. Subsequently, machine learning methods were employed to prioritize the core candidate genes. Additionally, important metabolic pathways were identified using Gene Set Enrichment Analysis (GSEA). Furthermore, protein-protein interaction (PPI) studies were used to identify the downstream targets of the core genes. Mendelian randomization (MR) analysis was used to investigate the regulatory mechanisms of CLL’s core genes. ZDHHC8 expression was markedly elevated in CLL patients and was linked to a poor prognosis. CAV1 is a key downstream target of ZDHHC8 in regulating CLL proliferation and anti-apoptosis. Mechanistically, ZDHHC8 expression grouping-based GSEA showed a notable enrichment of cellular lipid metabolism pathways, indicating that this is a major mechanism by which ZDHHC8 facilitates the development of CLL. MR analysis revealed substantial evidence of a positive causal connection between increased CAV1 expression and increased lipid metabolism. Further research has revealed that ZDHHC8 palmitoylates CAV1, activating cellular lipid metabolism to supply energy to cancer cells and driving the proliferation of malignant CLL.This work investigates the method by which ZDHHC8 regulates lipid metabolism via palmitoylation, specifically the involvement of the ZDHHC8/CAV1/lipid metabolism axis in CLL malignant proliferation, which could be a viable therapeutic target for CLL.