The role of GPD1L in colorectal cancer progression: A systematic review of its expression, molecular mechanisms, and prognostic significance.

Abstract

e15728 Background: Colorectal cancer (CRC) continues to be one of the leading causes of cancer-associated morbidity and mortality globally. Despite advances in screening and treatment, many patients develop advanced disease marked by invasion, metastasis, and poor long-term outcomes. Increasing evidence suggests that metabolic dysregulation and hypoxia-related signaling play important roles in CRC progression. Glycerol-3-phosphate dehydrogenase 1-like (GPD1L)–a metabolism-related gene related to redox homeostasis signaling in cells, has also been proposed to be a targeted tumor suppressor in several tumors. However, its biological and clinical relevance in CRC has not been comprehensively evaluated. Methods: We conducted a systematic review of literature through January 2026 on PubMed, Scopus and Web of Science. Studies evaluating GPD1L expression, functional effects, or prognostic significance in CRC using bioinformatic datasets, clinical samples, or experimental models were included. We extracted data from studies on study design, datasets or cohorts, molecular mechanisms, and clinical outcomes, and findings were synthesized descriptively. Results: Eight studies were included, comprising over 1,500 CRC tumors and more than 150 normal colorectal samples from TCGA, GEO, and institutional cohorts. All studies demonstrated significantly lower GPD1L expression in CRC compared with normal tissue ( p < 0.01). Low GPD1L expression was consistently associated with advanced TNM stage and lymph node metastasis ( p < 0.05). Survival analyses showed that reduced GPD1L expression predicted worse overall survival, with reported hazard ratios ranging from 1.6 to 2.4, and poorer recurrence-free survival (HR 1.5–2.1), remaining significant after multivariable adjustment ( p ≤0.01). Functional studies revealed that GPD1L suppression increased CRC cell proliferation, migration, and invasion, whereas GPD1L overexpression reduced invasive capacity by approximately 40–55% ( p < 0.01). Mechanistically, GPD1L loss was linked to increased HIF-1α stability, upregulation of MMP9, and activation of metabolic and hypoxia-related pathways. Conclusions: GPD1L is consistently downregulated in colorectal cancer and is associated with aggressive disease features and significantly worse survival outcomes. Functional evidence supports a tumor-suppressive role for GPD1L through metabolic and hypoxia-driven mechanisms. These findings support GPD1L as a promising prognostic biomarker and potential therapeutic target in CRC.