In Silico Identification of Phenylacetaldehyde's Impact on Downregulating Malignancy-Associated Genes: A Promising Therapeutic Approach Against Colorectal Cancer

Background: Gut microbiota-derived metabolites, including phenylacetaldehyde (PAA), have demonstrated promising anti-cancer properties. Gene expression alterations play a critical role in colorectal cancer (CRC) progression, influencing tumor aggressiveness and patient survival outcomes. Objectives: This study aimed to investigate the potential of PAA in modulating the overexpression of genes associated with malignancy in CRC. Methods: A high-throughput transcriptomic dataset (GSE207618) was analyzed to identify PAA-responsive genes and their association with CRC progression. The protein-protein interaction (PPI) network was constructed to determine key hub genes with significant downregulation under PAA influence. Clinical data from the Cancer Genome Atlas (TCGA) were integrated to identify poor-prognosis genes, and co-expression network analysis was performed to explore molecular pathways linked to CRC progression. Results: Comparing the differential expression outcomes revealed that 54 genes have significant overexpression in CRC samples, whereas their expression levels decreased in the presence of PAA. Among these, nine key genes, including MCM2, MCM4, MCM6, MCM7, MCM10, PCNA, UHRF1, FEN1, and KIF11, were specified as hub genes based on the PPI network analysis, which play crucial roles in core pathways associated with CRC cell proliferation and progression. According to the Cox regression results, IFI30 and HSPA1B can be considered strong biomarkers related to the poor prognosis of CRC patients, as their expression showed a significant drop under PAA treatment. The co-expression networks predicted a potential connection between the expression levels of IFI30 and genes involved in cancer cell invasiveness and suppressing apoptosis. The pathways connected to the malignant processes have correlated with the expression levels of HSPA1B. Conclusions: The current study underscores the ability of PAA to downregulate oncogenes in CRC through transcriptomic modulation. Given its influence on cancer-related gene expression, PAA can represent a novel therapeutic candidate that needs further experimental validation for potential integration into CRC treatment strategies.