Why Is Colorectal Cancer Occurring Earlier? Metabolic Dysfunction, Underrecognized Carcinogens, and Emerging Controversies

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer diagnosed before 50 years of age, is increasing worldwide and represents a major challenge to current prevention and screening paradigms. While obesity and metabolic dysfunction are important contributors, EOCRC appears to arise from a complex interplay of genetic susceptibility, metabolic stress, early-life exposures, microbiome alterations, environmental factors, and potentially infectious agents. This review aims to critically examine recent epidemiologic, molecular, and multi-omics evidence on EOCRC etiology, integrate metabolic and exposomic hypotheses within a life-course framework, highlight ongoing controversies and methodological limitations, and discuss emerging challenges for risk stratification and prevention. Recent EOCRC-specific meta-analyses and cohort studies demonstrate moderate associations between EOCRC and obesity, central adiposity, insulin resistance, metabolic syndrome, and lifestyle factors such as alcohol use, sedentary behavior, and ultra-processed diets. Molecular and multi-omics studies reveal that EOCRC is enriched for chromosomal instability–driven tumors, metabolic and inflammatory signaling pathways, gut microbiome dysbiosis, and accelerated epigenetic aging, exceeding chronological age by more than a decade in some patients. In utero exposures, early-life anthropometry and metabolic dysfunction may contribute to EOCRC risk, potentially through developmental programming of metabolic and inflammatory pathways. Complementing metabolic dysfunction, growing attention has focused on the modern exposome, including antibiotics, micro- and nanoplastics, smoking, environmental pollutants, ionizing radiation exposure, and chronic infections. Notably, HPV has emerged as a potential, though still controversial, cofactor in EOCRC, with heterogeneous tissue-detection studies and limited age-stratified epidemiologic data underscoring the need for further investigation. Clinically, EOCRC remains largely symptom-driven, with frequent diagnostic delays and symptom misattribution contributing to advanced-stage presentation. EOCRC is a multifactorial malignancy driven by cumulative metabolic dysfunction and inflammatory stress interacting with environmental, microbial, and early-life exposures on a background of genetic susceptibility and accelerated epigenetic aging. Addressing the EOCRC epidemic will require integrated, life-course prevention strategies that move beyond age-based screening to incorporate metabolic health optimization, lifestyle and exposome modification, improved symptom recognition, and risk-adapted early detection.