TRIM34-Mediated Ubiquitination and Degradation of HIF-1A Regulates Glycolysis in Endothelial Cells, Inhibits Angiogenesis, and Relieves the Progression of Lung Fibrosis

Idiopathic interstitial pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by interstitial fibrosis, with poor prognosis and high mortality. TRIM34 is involved in the intracellular ubiquitination process, but its mechanism of action in IPF is currently unknown. The purpose of this study was to investigate the effect of TRIM34 on the IPF process and its mechanism. In this study, 5 mg/kg of bleomycin (BLM) was injected into the rat trachea to construct the IPF animal model, and 10 ng/mL of VEGF165 was added to human pulmonary microvascular endothelial cell (HPMECs) culture medium to construct the angiogenic cell model. The expression of proteins was detected by Western blot. The assessment of proliferation, angiogenesis, and fibrosis in HPMECs and rat lung tissue was conducted using EdU staining, scratch tests, angiogenesis tests, HE staining, and Masson staining. The research indicated a reduction in TRIM34 expression in IPF. Overexpression of TRIM34 significantly improved pulmonary inflammatory infiltration in IPF rats, restored alveolar structure, reduced Collagen deposition in lung tissue, upregulated the expression of E-cadherin, downregulated the expression of COL-I, COL-III, a-SMA, CD31, CD34, and VEGFA, and finally alleviated the progression of IPF in rats. In addition, overexpression of TRIM34 also inhibited VEGF-induced proliferation, migration, and angiogenesis of HPMECs by inhibiting glucose uptake and pyruvate, lactic acid, and ATP content of HPMECs. In terms of mechanism, Tianlongjie (TL) therapy promotes HIF-1A ubiquitination degradation by upregulating TRIM34 expression, thereby inhibiting glycolysis, reducing angiogenesis, and alleviating IPF progression. In conclusion, TL therapy inhibits angiogenesis by upregulating TRIM34 expression and ultimately alleviates IPF progression.

HIF‐1A; TRIM34; Tianlongjie; angiogenesis; glycolysis; idiopathic pulmonary fibrosis.