Researchers reveal new mechanisms of how fructose promotes colorectal cancer

Fructose, the most common food sweetener, is widely used in processed sugary beverages, candies, and baked goods. Excessive fructose intake is closely associated with metabolic diseases like obesity, diabetes, and fatty liver. Epidemiological studies have also shown that excessive fructose consumption increases the risk of colorectal cancer. However, the mechanisms of fructose in the progression of colorectal cancer remain unclear.

In a study published in Cell Metabolism, a research team led by Prof. PIAO Hailong from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS), in collaboration with the research teams of Prof. BU Pengcheng from the Institute of Biophysics of CAS, and Prof. SHEN Xian from Wenzhou Medical University, have uncovered new mechanisms by how fructose inhibits the polarization of M1-type tumor-associated macrophages (M1-like TAMs), thereby promoting colorectal cancer development.

The researchers found that the metabolic rate of fructose in macrophages, in contrast to that of hepatocytes (primary cells for fructose metabolism), was significantly slower. Using ¹³C-labeled fructose metabolic flux analysis and targeted metabolomics, they demonstrated that fructose likely inhibited the polarization of M1-like TAMs through hexokinase 2 (HK2) rather than its downstream metabolic products.

Furthermore, the researchers revealed that fructose promoted the interaction between HK2 and inositol 1,4,5-trisphophate receptor type 3 (ITPR3), a key protein component of Ca²⁺ transport channels in the endoplasmic reticulum. This interaction significantly reduced the formation of mitochondria-associated endoplasmic reticulum membranes (MAM) and decreased the concentration of calcium in the cytoplasm and mitochondria. Knocking out glucose transporter 5 (GLUT5) or supplementing a mutational HK2 in bone marrow-derived macrophages with reduced HK2 expression reversed the downregulatory effects of fructose in MAM and calcium level.

In addition, the researchers observed that the interaction between HK2 and ITPR3 lowered calcium levels in mitochondria and cytoplasm, suppressing the activation of p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 1 (STAT1), and NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. This inhibition ultimately blocked M1-like TAM polarization.

"Our study reveals a novel role of fructose as a signaling molecule that promotes colorectal cancer by inhibiting M1-like TAMs polarization," said Prof. PIAO.