Paeoniflorin Alleviates Pulmonary Arterial Hypertension by Suppressing TRIM24 ‐Mediated SIRT1 Ubiquitination and NLRP3 Inflammasome Activation

This study aimed to investigate the molecular mechanism by which tripartite motif‐containing 24 (TRIM24) regulates the ubiquitination of sirtuin 1 (SIRT1) and to explore the protective effect of paeoniflorin (PF) on pulmonary arterial hypertension (PAH). Bioinformatics analysis identified TRIM24 and SIRT1 as key targets of PF. A PAH rat model was established by SU5416 (Su) injection combined with chronic hypoxia (Hx). These model rats were then treated with PF and/or subjected to overexpression of TRIM24 or SIRT1. TRIM24 and SIRT1 expression were assessed by reverse transcription quantitative PCR (RT‐qPCR) and immunohistochemistry. Lung vascular remodeling was evaluated by hemodynamic analysis and hematoxylin–eosin (HE) staining. Inflammatory cytokine levels (interleukin‐1β, interleukin‐6, tumor necrosis factor‐α) in lung tissues were measured. In vitro, hypoxia‐exposed human pulmonary artery endothelial cells (HPAECs) were used to evaluate PF effects on cell viability (CCK‐8), migration (scratch assay), and protein expression (Western blot). Ubiquitination and protein stability assays demonstrated that TRIM24 promoted SIRT1 protein degradation. TRIM24 inhibited SIRT1‐mediated autophagy, thereby activating the NOD‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome. Conversely, SIRT1 upregulation enhanced autophagy and suppressed NLRP3 activation. PF alleviated PAH and endothelial dysfunction by downregulating TRIM24 and preserving SIRT1 function. These findings reveal a novel mechanism by which PF protects against PAH via the TRIM24/SIRT1/NLRP3 axis.