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Drugging a transcription factor to treat asthma
In the lungs of asthma patients, too many goblet cells differentiate (a process called metaplasia) and consequently produce excess mucus in response to various inflammatory signals. The transcription factor FOXM1 is upstream of the transcription factor SPDEF, which is important for airway goblet cell differentiation. Sun et al. identified and characterized a small molecule called RCM-1 that prevented the nuclear translocation of FOXM1 in mice sensitized to house dust mite allergens. In these mice, RCM-1 also prevented airway hyperreactivity and inflammation and improved lung function. IL-13 signaling triggers goblet cell metaplasia, and RCM-1 prevented this response in mice that received IL-13 intranasally. Thus, RCM-1 could be used to treat asthma and other chronic pulmonary disorders associated with goblet cell metaplasia.
Goblet cell metaplasia and excessive mucus secretion associated with asthma, cystic fibrosis, and chronic obstructive pulmonary disease contribute to morbidity and mortality worldwide. We performed a high-throughput screen to identify small molecules targeting a transcriptional network critical for the differentiation of goblet cells in response to allergens. We identified RCM-1, a nontoxic small molecule that inhibited goblet cell metaplasia and excessive mucus production in mice after exposure to allergens. RCM-1 blocked the nuclear localization and increased the proteasomal degradation of Forkhead box M1 (FOXM1), a transcription factor critical for the differentiation of goblet cells from airway progenitor cells. RCM-1 reduced airway resistance, increased lung compliance, and decreased proinflammatory cytokine production in mice exposed to the house dust mite and interleukin-13 (IL-13), which triggers goblet cell metaplasia. In cultured airway epithelial cells and in mice, RCM-1 reduced IL-13 and STAT6 (signal transducer and activator of transcription 6) signaling and prevented the expression of the STAT6 target genes Spdef and Foxa3, which are key transcriptional regulators of goblet cell differentiation. These results suggest that RCM-1 is an inhibitor of goblet cell metaplasia and IL-13 signaling, providing a new therapeutic candidate to treat patients with asthma and other chronic airway diseases.