Introduction

Metabolomics has emerged as a powerful tool in cancer research, enabling the comprehensive profiling of metabolites that reflect cellular processes in health and disease. One of the key insights from this field is that cancer cells, including those in colorectal cancer (CRC), undergo substantial metabolic reprogramming to support uncontrolled growth and proliferation, known as hallmarks of cancer [1]. These alterations include shifts in energy metabolism, biosynthetic demands and redox balance. In CRC, metabolic changes may also be modulated by the gut microbiota, which can influence the production and degradation of the metabolites within the intestinal lumen [2–4].

CRC arises from precursor lesions such as advanced adenomas and advanced serrated polyps through the adenoma-carcinoma (85%) or serrated pathway (15%), respectively [5]. CRC and those precursor lesions are collectively referred to as advanced colorectal neoplasia. Since the five-year survival rate drops from 90% for stage I to 14% for stage IV disease, early detection and removal of CRC and precursor lesions can lower incidence and improve survival [6, 7]. Faecal immunochemical testing (FIT) is widely used in European population-based screening programs to identify individuals at high-risk for CRC or its advanced precursors. However, FIT has limited sensitivity for advanced adenomas and serrated polyps, combined with modest specificity for CRC, leading to missed lesions and a high number of unnecessary colonoscopies [8, 9]. This highlights the need for novel, non-invasive biomarkers that can improve screening accuracy.

Among the many metabolic changes identified in CRC, alterations in amino acid concentrations and pathways have emerged as one of the most frequently reported findings. Differences in amino acid profiles between CRC patients and controls have been reported across matrices such as faeces, serum, and urine, indicating potential as non-invasive biomarkers [10–12]. However, a systematic, cross-matrix comparison of these amino acid alterations is currently lacking. This gap limits the ability to integrate findings across matrices and to assess the robustness and translational relevance of amino acids as reliable biomarkers for advanced colorectal neoplasia.

This systematic review aimed to summarise current evidence on amino acid profile alterations in patients with advanced colorectal neoplasia and controls, aiming to identify neoplasia-specific profiles. In addition, we evaluated the extent of overlap in differential amino acids between matrices and assessed the diagnostic potential of amino acids as non-invasive biomarkers for advanced colorectal neoplasia detection.