Disulfidptosis in heart failure: an emerging mechanism awaiting exploration

Figures

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  Figure 1. Integrated mechanistic schematic of potential disulfidptosis in heart failure. This schematic illustrates the proposed SLC7A11-NADPH-disulfide stress-F-actin collapse cascade in the pathological context of HF. HF-related metabolic remodeling, mitochondrial dysfunction, redox imbalance, and cytoskeletal instability may create a permissive environment for disulfidptosis-like injury.

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  Figure 2. Different mechanisms of cardiomyocyte death. This figure summarizes major regulated cardiomyocyte death pathways involved in HF, including apoptosis, ferroptosis, pyroptosis, necroptosis, autophagy-dependent injury, cuproptosis and the predicted disulfidptosis pathway. Disulfidptosis may represent a cytoskeleton-centered injury mechanism linking SLC7A11-mediated cystine uptake, NADPH insufficiency, disulfide stress, and F-actin collapse. Its occurrence in cardiomyocytes and failing myocardium remains to be experimentally validated.

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  Figure 3. Cross-cohort reproducibility and independent validation of high-value disulfidptosis-related transcriptional signals in failing myocardium. (A) Cross-cohort expression patterns of nine candidate genes across three primary RNA-sequencing cohorts (GSE116250, GSE55296, and GSE135055) and the independent validation cohort GSE57338. Each cohort was analysed separately. Red and blue circles indicate higher and lower expression, respectively, in heart failure (HF) relative to normal myocardium. Circle size is proportional to −log10(FDR) and therefore represents the strength of statistical evidence rather than the magnitude of the expression difference. Black circle borders indicate FDR < 0.05, whereas grey borders indicate FDR ≥ 0.05. “NA” indicates that the corresponding gene was unavailable or could not be evaluated in that cohort. (B) Independent cross-platform validation in GSE57338. Horizontal bars represent the mean normalized log2 expression difference between HF and normal myocardium (HF−Normal). Positive red bars indicate higher expression in HF, whereas negative blue bars indicate lower expression in HF. Tier 1 genes were defined as genes showing concordant expression…

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  Figure 4. Metabolic–redox–cytoskeletal transcriptional programmes in heart failure. (A) Scores of the NADPH-generating, redox-buffering, and actin-cytoskeletal programmes in normal and heart-failure myocardium across four cohorts. Scores were calculated independently within each cohort using mean gene Z scores. Groups were compared by two-sided Wilcoxon rank-sum tests with Benjamini–Hochberg correction across 12 comparisons. (B) Meta-analysed Spearman correlations between the three programmes and heart-failure pathological pathways. Correlations were calculated within HF samples after removing overlapping genes and combined using random-effects models after Fisher z transformation. Red and blue indicate positive and negative correlations, respectively. FDR < 0.05, FDR < 0.01, FDR < 0.001.