Isopimpinellin: A Promising Treatment for Colitis‐Related Colorectal Cancer That Targets <scp>ALOX5</scp> ‐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.