Colitis-associated colorectal cancer (CAC) is a serious complication of inflammatory bowel disease (IBD), a group of chronic conditions that cause persistent inflammation in the gut lining. Unlike ordinary colorectal cancer, CAC typically involves multiple tumor sites and carries a worse prognosis, making it especially important to understand and treat.
The progression from IBD to CAC follows a recognizable sequence: the intestinal lining first undergoes chronic damage, then mild abnormal cell growth, then severe abnormal growth, and finally full-blown cancer. This slow transformation provides a window of opportunity for early detection and intervention if the right molecular signals are identified in time.
This review focuses on a key driver of this transformation that has been underappreciated: lipid metabolism reprogramming, the way cancer cells rewire their fat-processing machinery to fuel their own growth. By systematically examining how fatty acids, cholesterol, phospholipids, and sphingolipids are altered in CAC, the authors aim to identify new targets for therapy and prevention.
Tumor cells are highly energy-hungry. They require large amounts of lipids, including phospholipids for building cell membranes, cholesterol for signaling, sphingolipids for structural support, and triglycerides for energy storage. To meet these demands, cancer cells dramatically increase their lipid production and uptake, creating an environment that also feeds inflammation.
The result is a self-reinforcing cycle often described as the metabolism-inflammation-carcinogenesis axis. Lipid imbalances activate inflammatory signals, which in turn promote more abnormal lipid metabolism, which drives further tumor growth. This cycle also disrupts the gut microbiota, further fueling both inflammation and cancer development.
High-fat diets (HFD) can accelerate this process, though the exact effects depend on the type of fat consumed and the timing of exposure. Early high-fat feeding in experimental models significantly increases tumor number and worsens differentiation, whereas in some genetic models, certain unsaturated fats may paradoxically reduce tumor burden, highlighting the complexity of diet-cancer interactions in CAC.
Fatty acid synthase (FASN), the enzyme that builds fatty acids from scratch inside cells, is prominently overexpressed in CAC. Its overactivation promotes tumor growth, invasion, and resistance to treatment. Concurrently, CPT1A, the enzyme that breaks down fatty acids for energy, is also dysregulated, disrupting the normal balance between fat-building and fat-burning and forming a metabolic imbalance that favors tumor survival.
Fatty acid-binding proteins (FABPs) are molecular chaperones that ferry fats around inside cells. Multiple FABPs are abnormally expressed in CAC: FABP1 overexpression promotes tumor formation, FABP4 amplifies oncogenic signals through the AKT and MAPK pathways, and FABP5 plays a more nuanced role, partially counteracting FABP1 while also being activated by hypoxia to increase fat storage and tumor cell migration.
Cholesterol also plays a critical role. The low-density lipoprotein receptor (LDLR) is markedly upregulated in colon tumors, allowing cancer cells to grab more cholesterol from the bloodstream. Excess cholesterol activates the NLRP3 inflammasome, releasing inflammatory cytokines IL-1beta and IL-18 that further reshape the tumor microenvironment. A high-cholesterol diet has been linked to worsened inflammation and increased tumor burden in experimental models.
Phosphatidic acid (PA) is a lipid messenger that sits at a crossroads of cell growth and death signaling. The enzyme LPIN1 controls the balance between PA and another signaling lipid called diacylglycerol (DAG), and also regulates the production of IL-23, a cytokine that maintains pro-inflammatory T helper 17 cells. Meanwhile, phospholipase D1 (PLD1) generates PA from membrane phospholipids and is overactive in CAC, activating the growth-promoting mTORC1 pathway.
Sphingolipids are a family of complex fats essential for maintaining the gut mucosal barrier and regulating cell fate decisions. In CAC, the SphK1/S1P axis (sphingosine kinase 1 and its product sphingosine-1-phosphate) is upregulated, promoting pro-inflammatory macrophage polarization and sustaining the NF-kB-STAT3 signaling loop that perpetuates chronic inflammation. Ceramide, a pro-apoptotic sphingolipid, is paradoxically downregulated, tipping the balance toward tumor cell survival.
Sphingomyelin synthase 2 (SMS2) is consistently overexpressed in CAC tumors. When SMS2 is deleted in mouse models, there is significantly less colon tumor formation. SMS2 deletion causes ceramide to accumulate (which triggers cell death via the PP2A-Akt pathway) while also suppressing the Wnt/beta-catenin pathway and reducing COX-2 expression, two other key drivers of colorectal cancer.
Several additional proteins regulate the broader lipid reprogramming network in CAC. HIF-1alpha, the master regulator of cellular responses to low oxygen, promotes fat uptake and storage while suppressing fat breakdown, making tumor cells more proliferative and migratory. HAKAI, an E3 ubiquitin ligase, acts as a natural brake on FASN by tagging it for degradation, but this suppressive function is lost in CAC. PTPRO, a tumor-suppressor phosphatase, is also downregulated, with its loss accelerating tumor growth and liver metastasis in animal models.
The gut microbiota serves as a critical bridge between diet, lipid metabolism, and CAC development. Gut bacteria convert primary bile acids into secondary bile acids such as deoxycholic acid (DCA), which at high concentrations damages DNA and promotes tumor growth. Beneficial bacteria produce short-chain fatty acids like butyrate, which nourishes the gut lining and suppresses NF-kB and NLRP3 inflammation. In CAC, dysbiosis (microbial imbalance) reduces butyrate-producing bacteria, weakening the gut barrier and amplifying the inflammatory drive toward cancer.
Bacterial lipopolysaccharides and conjugated linoleic acid produced by gut bacteria can also directly modulate FASN activity and PPARgamma signaling in host cells. This complex microbiota-host metabolic dialogue is disrupted in CAC, creating a metabolic microenvironment that strongly favors tumor development rather than normal gut homeostasis.
Lipid metabolic pathways represent promising new therapeutic targets for CAC. Statins, which inhibit cholesterol biosynthesis, have shown anti-cancer effects in preclinical models including induction of tumor cell apoptosis and inhibition of angiogenesis. Simvastatin in particular can enhance LDL receptor expression in ways that further limit tumor cholesterol availability. However, clinical translation remains complicated by dose-dependent side effects and variable patient responses, particularly in IBD patients where statins may alter bile acid composition and worsen mucosal inflammation.
Targeting the SOAT1 enzyme (sterol O-acyltransferase 1) with the inhibitor avasimibe reduces colorectal cancer cell viability by disrupting cholesterol storage. Inhibiting PLD1 or PLD2 (phospholipase D enzymes that generate phosphatidic acid) markedly reduces tumor burden in mouse models of CAC, providing a rationale for developing pharmacological PLD inhibitors as CAC therapies.
On the fatty acid side, targeting the FAO-Drp1 axis (fatty acid oxidation combined with inhibition of mitochondrial fission protein Drp1) could block tumor cell survival mechanisms. The Drp1 inhibitor Mdivi-1 suppresses oxidative metabolism in colon cancer cells, induces cell cycle arrest, and triggers apoptosis. Combining lipid metabolism-targeted agents with conventional chemotherapy (such as 5-fluorouracil) or immunotherapy may offer synergistic benefits for CAC patients with currently limited treatment options.