Isopimpinellin: A Promising Treatment for Colitis‐Related Colorectal Cancer That Targets ALOX5‐Mediated Macrophage Polarization

Colitis‐associated colon cancer (CAC) is a malignant tumor caused by long‐term inflammation. Isopimpinellin, known for its anti‐inflammatory and anti‐tumor properties in areas beyond CAC, may target arachidonate 5‐lipoxygenase (ALOX5). This study aims to investigate the regulation of the isopimpinellin/ALOX5 axis in CAC. CAC mouse model was induced through intraperitoneal injection of 10 mg/kg azoxymethane and administration of 2% dextran sulfate sodium salt in drinking water. Oral isopimpinellin (50 or 100 mg/kg) was administered. ALOX5 expression was upregulated via adenovirus delivery. Non‐targeted metabolomics was employed to analyze the influence of isopimpinellin on metabolic profiles. The 100 mg/kg isopimpinellin demonstrated promising therapeutic effects, as evidenced by protected colon tissue and the inhibition of inflammation and tumor. Pro‐inflammatory factors were elevated in para‐carcinoma tissues, while anti‐inflammatory cytokines were upregulated in cancer tissues. M2 macrophages were increased in cancer tissues, whereas M1 macrophages were elevated in para‐carcinoma tissues. Oral administration of isopimpinellin suppressed M2 polarization and M1 polarization in macrophages of cancer and para‐carcinoma tissues, respectively. The overexpression of ALOX5, which was expressed in macrophages in the colon, abolished the effects of isopimpinellin. Finally, isopimpinellin altered metabolism in CAC mice, involving cancer‐related metabolic processes and signaling pathways in cancer tissues, and amino acid metabolic pathways in para‐carcinoma tissues. Isopimpinellin inhibits macrophage M1 polarization in cancer tissues and M2 polarization in para‐carcinoma tissues by targeting ALOX5, thereby inhibiting tumor growth and inflammatory response in CAC mice. This study provides strategies for the treatment of CAC.