Idiopathic pulmonary fibrosis is a rapidly progressing and fatal lung disease, with unclear pathogenesis and a lack of safe and effective treatment drugs, posing a major challenge to human health. Not long ago, Chinese scientists made an important breakthrough in this field: revealing the cellular and molecular mechanisms of idiopathic pulmonary fibrosis and identifying new targets that have the potential to treat pulmonary fibrosis. This achievement was led by Tang Nan Laboratory of Beijing Institute of Life Sciences/Biomedical Interdisciplinary Research Institute of Tsinghua University, and completed in cooperation with Dai Huaping's team of China-Japan Friendship Hospital and the R&D team of Primu Biotechnology Co., Ltd. Recently, relevant papers were published online in the international academic journal Cell Stem Cell. Clinical studies have shown that during the progression of idiopathic pulmonary fibrosis, the lesions start from the edges of lung tissue and continue to spread towards the center, leading to a progressive and irreversible decline in lung function. In 2020, Tang Nan's laboratory successfully constructed a progressive pulmonary fibrosis mouse model that can highly simulate the characteristics of idiopathic pulmonary fibrosis, and demonstrated for the first time internationally that alveolar regeneration disorder causes activated alveolar stem cells to be trapped in an intermediate state of differentiation after injury, exposing them to continuously increasing mechanical tension. This is a key driving factor in inducing pulmonary fibrosis to start from the edge of lung lobes and continuously progress towards the center of the lung. Multiple international teams' studies have also shown that intermediate state alveolar stem cells induced by lung injury are closely related to pulmonary fibrosis. However, the cellular and molecular mechanisms by which intermediate state alveolar stem cells trigger pulmonary fibrosis remain an unsolved mystery. To this end, Tang Nan's team conducted in-depth exploration. They first discovered that as the proportion of alveolar stem cells in the intermediate state increased from the edge to the center, pulmonary fibrosis also progressed from the edge to the center. Due to the high expression of multiple pro fibrotic genes in intermediate state alveolar stem cells, these stem cells are likely to directly participate in regulating fibrosis by secreting pro fibrotic factors, "said Tang Nan. Which factor regulates the occurrence of idiopathic pulmonary fibrosis? Researchers have targeted the dual regulated protein AREG, which is specifically expressed in intermediate state alveolar stem cells. To demonstrate the role of AREG in pulmonary fibrosis, researchers specifically knocked out AREG from alveolar stem cells in an animal model of progressive pulmonary fibrosis, which significantly inhibited the occurrence of pulmonary fibrosis and improved the survival rate of the endpoint animals. Meanwhile, they consistently induced AREG overexpression in alveolar stem cells of healthy mice, significantly leading to the occurrence of pulmonary fibrosis. Research has shown that AREG is a necessary and sufficient condition for driving the occurrence and progression of pulmonary fibrosis. Through a series of in vitro cell experiments and in vivo animal models, researchers have also demonstrated that intermediate state alveolar stem cells directly act on fibroblasts expressing EGFR (epidermal growth factor receptor) through sustained secretion of AREG, promoting the occurrence of pulmonary fibrosis. In the lung samples of patients, researchers obtained the same results. To further verify the relationship between AREG and the occurrence of idiopathic pulmonary fibrosis, researchers analyzed the levels of AREG in the serum of 103 patients. The results showed that the level of AREG in the serum of patients with idiopathic pulmonary fibrosis was significantly elevated and negatively correlated with the patient's lung function. In addition, the level of serum AREG is significantly positively correlated with the severity of the patient's condition. In terms of drug research, researchers have effectively blocked AREG by using neutralizing antibodies, which can significantly inhibit the occurrence and development of pulmonary fibrosis in mice and improve animal survival rates. This discovery highlights the therapeutic potential of anti AREG antibodies in slowing down the progression of idiopathic pulmonary fibrosis and provides a promising and safe treatment strategy. (New Society)