Activating Cannabinoid receptor 2 alleviates iron overload-induced liver damage via dual modulation of STAT3/hepcidin and Nrf2/FPN1 pathways.

Iron overload-related liver injury is a major clinical problem in hereditary hemochromatosis, transfusional siderosis, and chronic liver diseases, yet current treatments such as iron chelation therapy and phlebotomy are limited by safety and efficacy issues. Cannabinoid receptor type 2 (CB2R) has been implicated in the regulation of iron metabolism, but its role and underlying mechanism in iron overload remain unclear. Here, we investigated whether CB2R can prevent liver damage caused by iron overload and explored its potential mechanism. Male C57BL/6J mice received 100 mg/kg iron-dextran intraperitoneally to establish an iron overload model. Liver damage and iron deposition were evaluated via histology, serum biochemistry, and molecular analyses. Further studies using primary hepatocytes and Kupffer cells exposed to ferric ammonium citrate (FAC) were performed to explore cell type-specific mechanisms in vitro. Pharmacological CB2R activation with the selective agonist JWH133 reduced liver iron deposition, oxidative stress, and inflammation, whereas CB2R-knockout (KO) exacerbated these phenotypes. Mechanistically, CB2R activation suppressed signal transducer and activator of transcription 3 (STAT3)-dependent hepcidin transcription in hepatocytes, thereby enhancing ferroportin 1 (FPN1)-mediated iron efflux. Concurrently, CB2R promoted nuclear factor erythroid 2-related factor 2 (Nrf2)/FPN1 signaling in Kupffer cells, decreasing the labile iron pool. These findings identify CB2R as a key regulator of hepatic iron homeostasis and suggest that targeting CB2R may offer a novel therapeutic strategy for iron overload-related diseases.