Abstract In recent years, metabolic reprogramming has emerged as a significant breakthrough in elucidating the onset and progression of gastrointestinal (GI) malignancies. As central regulatory hubs for lipid metabolism, sterol regulatory element binding proteins (SREBPs) integrate dietary metabolic signals and carcinogenic stimuli through subtype-specific mechanisms, thereby promoting malignant tumour phenotypes. In this review, we first present the molecular background, structural characteristics, and posttranscriptional regulatory networks associated with SREBPs. We subsequently describe a systematic analysis of the distinct activation patterns of SREBPs in liver, gastric, colorectal, and other gastrointestinal cancers. Furthermore, we explore targeted intervention strategies for different SREBP subtypes, including small molecule inhibitors (such as fatostatin, which inhibits SREBP cleavage), natural compounds (such as berberine, which modulates the AMPK/mTOR pathway), and statin-mediated inhibition of the mevalonic acid pathway. These strategies may enhance tumour cell sensitivity to chemotherapeutic agents (such as 5-FU, gezil, and tabine) and improve the response to synergistic chemoradiotherapy by reversing adaptive metabolic resistance driven by the tumour microenvironment. Through this review, we hope to provide new insights into precise interventions targeting various subtypes of the SREBP molecule.