The effect of cuproptosis-related gene Atox1 on cardiac hypertrophy in heart failure was investigated based on bioinformatics analysis.

Heart failure (HF) represents the final stage of multiple cardiovascular diseases. Cuproptosis may play an important role in the progression of HF. This study aimed to identify cuproptosis-related biomarkers in HF and elucidate their potential regulatory mechanisms. We downloaded the HF-related bulk dataset from the GEO database for performing WGCNA and differential analysis. A total of 5,563 HF-related co-expressed genes were identified. By intersecting the above genes with cuproptosis-associated genes, we identified three candidates (DBT, Atox1 and DLD) that are potentially involved in cardiac hypertrophy in HF. Among them, DBT and DLD were lowly expressed whereas Atox1 was highly expressed in the disease group. We selected Atox1 for subsequent analysis. Transverse aortic constriction (TAC) method was applied for establishing a mouse model of HF-associated cardiac hypertrophy. In the model mice, we found significantly overexpressed Atox1 (fold change = 3.47) by qRT-PCR and increased levels of cuproptosis marker proteins SLC31A1 and FDX1 as well as Dlat aggregation. To further examine the action mechanism of Atox1, cardiomyocytes (H9c2) were treated with Ang II to simulate cardiac hypertrophy in vitro, followed by ATOX1 knockdown. It was found that low expression of Atox1 inhibited cuproptosis and suppressed cardiomyocyte hypertrophy. When cuproptosis was activated in Ang II + si-Atox1 group using elesclomol + CuCl(2), cardiomyocyte hypertrophy was enhanced, while Atox1 expression remained unchanged. In summary, Atox1 plays a significant role in HF-associated cardiac hypertrophy and can regulate cuproptosis.