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Endothelial CDC42 deficiency aggravates pulmonary fibrosis via the PPARα-mediated lipid accumulation and cellular dysfunction in systemic sclerosis

ABSTRACT: Systemic sclerosis (SSc) is an autoimmune disease that causes vascular lesions and fibrosis in several organs, including the skin and lungs. Currently, therapy options for SSc-associated interstitial lung disease (SSc-ILD) are limited. Endothelial cells, notably their proliferation and migratory capacities, play an important role in angiogenesis and tissue regeneration. Cell Division Cycle 42 (CDC42), a member of the small GTPase family, regulates cell cycle and metabolism. However, its function and mechanism in SSc-ILD remain unknown. We found that decreased CDC42 expression in endothelial cells is a common feature in human patients with SSc-ILD and in bleomycin (BLM)-induced SSc mouse model. CDC42 deficiency increased BLM-induced endothelial lipid accumulation and endothelial dysfunction, aggravating pulmonary fibrosis. Conversely, endothelial cell-specific overexpression of Cdc42 effectively improved pulmonary vascular permeability and reduced fibrosis in mice. Mechanistically, Cdc42 directly binds Signal Transduction and Activation Factor 3 (STAT3), reducing its nuclear translocation and thereby inhibiting Peroxisome Proliferator-Activated Receptor Alpha (PPARα) and Fatty Acid Binding Protein 4 (FABP4) transcription and expression, which improves lipid accumulation and endothelial cell function. This study demonstrates that Cdc42 deficiency exacerbates BLM-induced endothelial lipid accumulation and dysfunction by regulating the STAT3-PPARα-FABP4 axis, thereby worsening pulmonary fibrosis. Targeting this signaling axis offers a novel perspective and potential intervention strategy for SSc-ILD treatment.

ORGANISM(S): Homo Sapiens

SUBMITTER: Guodong Hu

PROVIDER: PXD075726 | iProX | Mon Mar 16 00:00:00 GMT 2026

REPOSITORIES: iProX

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