Work

USP24 and NF-κB formed a positive regulatory loop increases BMP4 to induce cardiac fibrosis during lung cancer progression

Year: 2026

Type: article

Abstract: Cardiovascular diseases (CVD) and cancer are the leading causes of death worldwide each year. This study showed that EGFR L858R -induced lung cancer mice exhibited reduced heart function, which could be improved by knocking out USP24 or treating with a specific USP24 inhibitor, USP24-i-101. Bone morphogenetic protein 4 (BMP4), a member of the TGF-β superfamily, in cancer cells and M2 macrophages, is inhibited by USP24-i-101 or by silencing USP24. NF-κB can be recruited to the promoter of BMP4 to enhance its transcription activity. There is a positive feedback regulation between USP24 and NF-κB, increasing transcriptional activity to induce BMP4 expression in cancer cells and M2 macrophages. Secreted BMP4 from macrophages and cancer cells activates the SMAD pathway in cardiomyocytes, inducing fibrosis-related gene expression. In cardiac myoblasts, H9c2 cells, USP24 is also positively feedback regulated with BRD7 to activate the Wnt/β-catenin pathway, thereby inducing fibrosis-related gene expression. In summary, the positive feedback regulation between USP24 and NF-κB in lung cancer cells and M2 macrophages enhances BMP4 expression, causing fibrosis of cardiac myoblasts. Additionally, the positive feedback regulation between USP24 and BRD7 in cardiac myocytes activates the Wnt/β-catenin pathway, leading to fibrosis of myoblasts. Targeting USP24 with USP24-i-101 in lung cancer patients may improve cardiac activity by inhibiting heart tissue fibrosis.

Source: Cell Death Discovery

DOI: 10.1038/s41420-026-03438-8