Histone lactylation-associated gene FASN promotes prostate cancer progression through NF-κB signaling pathway

Our study aimed to investigate the role of FASN, a gene implicated in lactate metabolism and histone lactylation, in prostate cancer (PCa) progression. Differentially expressed gene (DEG) analysis was conducted on histone lactylation-associated genes in the TCGA-PRAD cohort. Subsequently, molecular subtypes of PCa were identified using consensus clustering analysis. A prognostic model was constructed using LASSO and Cox regression analyses based on histone lactylation-associated DEGs. Integrated weighted gene co-expression network analysis (WGCNA) and multivariate Cox regression analysis were used to identify core histone lactylation-associated DEGs associated with PCa progression and to systematically characterize their biological functions and immunoregulatory roles through immune infiltration assessment and functional enrichment. The diagnostic value of FASN was assessed using receiver operating characteristic (ROC) curve analysis, and its prognostic significance was determined using Kaplan–Meier analysis. The AUCell package was used to evaluate the activity of the histone lactylation pathway in different cell clusters, and cellular functional experiments were performed to verify the biological role of FASN. Molecular docking was used to screen FASN-targeting compounds. Thirty histone lactylation-associated DEGs were identified. FASN was further screened using WGCNA and multivariate Cox regression analyses. FASN was significantly upregulated in PCa and emerged as an independent prognostic risk factor. The prognostic model demonstrated robust predictive accuracy for patient outcomes. The results of ssGSEA indicated that FASN was enriched in the NF-κB signaling pathway. The expression of FASN was the highest in epithelial cells, and the AUCell algorithm results showed that the activity of the histone lactylation pathway was increased in PCa cells. Functional experiments demonstrated that knockdown of FASN markedly suppressed LNCaP cell proliferation, migration, and invasion, accompanied by reduced NF-κB signaling pathway activity, which was reversible upon lactate supplementation. Molecular docking identified bardoxolone methyl as a potent FASN inhibitor, and its antitumor efficacy was confirmed in vitro using flow cytometry, Transwell assays, and wound healing assays. Our multi-omics integrative analysis indicated FASN as a histone lactylation-associated oncogene that drives the progression of PCa. And FASN may regulate the level of histone lactylation by regulating the production of lactate, which in turn affects the activity of the NF-κB signaling pathway. In addition, molecular docking identified Bardoxolone Methyl as a potential compound capable of targeting and inhibiting FASN. In vitro experiments further showed that Bardoxolone Methyl could induce apoptosis and inhibit migration and invasion of PCa cells. Although the binding strength between Bardoxolone Methyl and FASN still needs to be demonstrated by relevant experiments, and its therapeutic effect on prostate cancer requires further validation through clinical trials, these findings provide a completely new direction for the treatment of prostate cancer.