BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC) (< 50 years) has been steadily rising, with a parallel increase in metastatic and invasive cases. To elucidate the molecular mechanisms underlying this aggressive phenotype, we performed comprehensive multi-omics profiling to delineate the distinct features of EOCRC, with a focus on key drivers of metastatic and invasive potential. METHODS: We initially characterized the genome, epigenome, and transcriptome of tumors from 515 (69 EOCRC and 446 late-onset CRC [LOCRC]) cases in The Cancer Genome Atlas. Key candidate molecules were further validated using RNA-seq and scRNA-seq data. Multi-omics profiling revealed PIWIL1/piRNA as a hallmark of EOCRC, with further validation through in vitro functional assays, transcriptomic profiling, and Kaplan-Meier survival analysis. RESULTS: EOCRC demonstrated a mutational landscape similar to that of LOCRC, with comparable oncogenic driver mutations and somatic copy-number alterations. However, EOCRC exhibited a higher frequency of deletion in chromosomes 6, 15, and 19 regions, along with metabolic reprogramming favoring aerobic glycolysis and lipid metabolism. Integrative transcriptomic and DNA methylation analyses identified six EOCRC-specific molecules, including PIWIL1. Notably, PIWIL1 was mainly expressed in epithelial cells, with lower expression in EOCRC versus LOCRC. Its downstream piRNAs (FR019019, FR019089, and FR132045) were also downregulated in EOCRC. Functional experiments demonstrated that FR019089/FR019019 overexpression suppressed migration and invasion. Clinically, low FR019089 levels correlated with significantly shorter progression-free and overall survival in EOCRC patients. Additionally, downstream pathways of FR019089 and FR019019 overexpression were enriched in anti-cancer-related signaling pathways. CONCLUSIONS: Our multi-omics approach yields novel insights into the molecular underpinnings of EOCRC and we characterize the role of PIWIL1-associated piRNAs in modulating EOCRC metastasis and invasion. FR019089 shows promise as a prognostic biomarker with potential clinical utility in the risk stratification and management of EOCRC patients.