Descubierta una nueva función para la proteína NOD1 en las enfermedades relacionadas con el hierro

New role discovered for NOD1 protein in iron-related diseases


Researchers from the Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, have published a new study about the novel function of NOD1 protein in iron homeostasis and in the process of cell death due to excess of iron

This important work represents the pavement of new avenues of research in the diagnosis and treatment of iron-related diseases, as well as the identification of new therapeutic targets to combat different immunometabolic pathologies.

The NOD1 protein, which had been previously related to inflammatory and cardiovascular pathologies, also plays an important role in the balance of iron levels in the body (homeostasis) and in the mechanisms of cell death due to excess iron (ferroptosis), according to a study recently released in the journal Biomedicine & Pharmacotherapy. The work has been led by Dr. Lisardo Boscá, a researcher at the Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), a joint center of CSIC and UAM and also a researcher at the Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV). Dr. Paloma Martín-Sanz, Dr. Carmen Delgado and Dr. Antonio Castrillo, researchers at the IIBM, have also participated in this work.

Iron is essential for the maintenance of life due to its contribution to important metabolic and cellular processes, such as oxygen transport, energy production, detoxification or even host defense. It is not surprising that its dysregulation, specifically its deficiency, leads to the development of different diseases, including anemia, infections, alterations of the immune system, inflammation and atherosclerosis. But not only is iron deficiency harmful to our body, but also its excess is quite detrimental, being the main cause of a specific cell death process known as ferroptosis.

The aim of this research work was to determine the role of protein NOD1 in iron metabolism and ferroptosis. Dr. Victoria Fernández-García, first author of this work, explains: "although previously it was known that NOD1 was involved in inflammatory and cardiovascular pathology, the specific connection between iron metabolism and atherosclerosis was still to be defined, focusing our attention on this protein". The role of monocytes and macrophages in iron homeostasis in an atherogenic context was studied, as well as the function of the organs that regulate the bioavailability of iron, employing both human and mouse models.

"Our findings highlight the relevant role of NOD1 in iron homeostasis and ferroptosis, especially under pro-atherogenic conditions," says Dr. Lisardo Boscá. Specifically, this group of researchers observed that mice lacking NOD1 and subjected to atherogenic conditions (by administering them a high-fat diet) had a marked decrease in iron content in several organs, including the spleen, the liver and the heart, which are regulatory tissues of iron metabolism. In these organs, a significant fibrosis was noticed due to the increase of proinflammatory cells in the areas of inflammation, including the atherosclerotic plaque. The authors found that an increase in the interleukin 8 receptor, also known as CXCR2, was implicated in the recruitment of macrophages to these areas of inflammation.

In addition, these researchers observed that the activation of NOD1 increased the levels of GPX4, and other iron-regulating proteins, leading to less ferroptosis.

Taken together, these results open new avenues of research for the diagnosis and treatment of iron-related diseases mediated by NOD1, as well as the identification of new pharmacological targets for the treatment of immunometabolic diseases, such as different types of anemia, including anemia falciform.