Exosomal miR-2137 from cadmium-treated hepatocytes drives renal ferropto-sis via GPX4 suppression and is alleviated by selenium

Qian WenMeiyan QiYanjun WuWeiwei JiLixing Zhan^*

• Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences (CAS), Shanghai, China

Cadmium (Cd) is a toxic heavy metal that has a significant impact on the liver and kidneys, rendering them highly susceptible to its toxic effects. However, the precise mechanism remains uncertain. Mice were exposed to Cd resulting severe ferroptosis and liver tissue damage via regulating hepatic GPX4 levels. It is noteworthy that de-spite the considerably lower concentration of Cd in the kidney compared to the liver, the oxidative damage observed in the exposed mice was significantly more severe in the kidney. It was therefore postulated that hepatic disorders may engage in such hepatorenal communication, thereby leading to the pathological phenotypes of distant organs under conditions of Cd exposure. The results of the mechanistic studies indi-cated that Cd-induced hepatocyte exosomes, which contain a variety of miRNAs produced by hepatocytes, such as miR-2137, etc., are capable of targeting renal GPX4 and reducing the level of GPX4 in renal cells. This resulted in the occurrence of ferroptosis in the kidneys. Injection of the appropriate dosage of Cd-induced exo-somes, derived from hepatocytes, is sufficient to induce kidney damage in vivo. Our data support the hypothesis that treatment with an antagomir targeting miR-2137 is capable of inhibiting this process. Moreover, our findings revealed that selenium (Se) supplementation was sufficient to protect against Cd-induced hepatic and renal tox-icity by elevating the expression level of selenoprotein GPX4 in vivo. In conclusion, we have identified liver-derived exosomes and their implications for hepatorenal communication under Cd exposure. This provides a new target for understanding the mechanism of Cd-induced hepatorenal communication. Our findings indicate that exosomes may serve as biomarkers and potential therapeutic agents for the exposure of Cd toxicity.