ML351

Chronic obstructive pulmonary disease‐associated pulmonary hypertension (COPD‐PH) is characterized by rapid progression of right ventricular (RV) dysfunction despite relatively preserved pulmonary hemodynamics, indicating the involvement of non‐pressure‐dependent mechanisms. Cigarette smoke (CS) is the primary etiological factor for COPD, but its direct contribution to RV failure under pressure overload remains unclear. We established a rat model of pulmonary artery banding (PAB), followed with CS exposure for 4 and 8 weeks. RV function and remodeling were evaluated using echocardiography, hemodynamic measurements, and histopathology, while molecular alterations were assessed via RNA sequencing. In vitro, neonatal rat RV cardiomyocytes (NRRCMs) and fibroblasts (NRRCFs) were treated with cigarette smoke extract (CSE), angiotensin II (Ang II), or transforming growth factor‐β (TGF‐β) to simulate mechanical and fibrotic stress. In PAB rats, CS exposure exacerbated RV dysfunction and promoted development of RV hypertrophy, fibrosis, and capillary rarefaction. Transcriptomic analysis revealed activation of the ALOX15‐ferroptosis pathway in RV tissue from CS‐exposed PAB rats. Immunofluorescence staining confirmed ALOX15's predominant localization in cardiomyocytes. In vitro, CSE amplified AngII‐induced ALOX15 upregulation in cardiomyocytes while increasing expression of cardiac stress markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Both Alox15 gene silencing and inhibition of ALOX15 enzymatic activity with ML351 significantly reduced ANP and BNP levels, confirming its functional role in these pathological changes. Our findings demonstrated that CS accelerated RV failure under pressure overload via direct cardiotoxic effects, with ALOX15‐mediated ferroptosis playing a key mechanistic role. This pathway represents a potential therapeutic target for mitigating RV dysfunction in COPD‐PH.