Impairment of aryl hydrocarbon receptor signalling promotes hepatic disorders in cancer cachexia

Background The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut–liver axis. Methods AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+) and from non‐cachectic mice (sham‐injected mice and non‐cachexia‐inducing [NC26] tumour‐bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6‐formylindolo(3,2‐b)carbazole [FICZ]) or an antibody neutralizing interleukin‐6 (IL‐6). Key mechanisms were validated in vitro on HepG2 cells. Results AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P