Selective transcript–protein discordance of glycolytic remodeling in human hypertrophic cardiomyopathy

Background Although metabolic reprogramming has attracted growing attention in hypertrophic cardiomyopathy (HCM), transcriptomic and proteomic studies have yielded conflicting views on glycolytic alterations. As a master transcriptional regulator of glycolytic genes, HIF1α remains poorly characterized in human HCM tissue. Methods We integrated four transcriptomic datasets, three proteomic datasets, and one phosphoproteomic dataset from publicly available human HCM cohorts. Glycolysis-, hypoxia-, and oxidative metabolism-related pathways were assessed by gene set enrichment analysis (GSEA). Transcript-protein concordance was evaluated by comparing the direction and magnitude of individual glycolytic enzyme changes across omics layers. Results Across all four transcriptomic cohorts, glycolysis-related programs were suppressed at the mRNA level (NES range: −1.1 to −1.7). HALLMARK_HYPOXIA was negatively enriched in four of five transcriptomic comparisons, and Semenza HIF1 targets showed the strongest suppression (NES = −1.99, P adj = 2.8 × 10 −4 ). At the protein level, alterations differed by pathway. Oxidative pathways (OXPHOS, TCA cycle, FAO) showed concordant downregulation at RNA and protein levels, whereas glycolytic enzymes displayed level-specific discordance. In Garmany 2023 paired samples, 5 of 12 glycolytic enzymes showed opposite RNA and protein directions, whereas the overall RNA–protein correlation was weak and non-significant ( r = −0.28, P = 0.38; n = 12) and was therefore considered descriptive. HK1 was the most prominent example of transcript-proteome decoupling, with reduced transcripts in four transcriptomic cohorts but increased protein levels across three independent proteomic platforms (Garmany TMT, Nollet LC-MS/MS, Lumish SomaScan). GSEA in Garmany 2023 demonstrated opposite enrichment patterns between transcriptome and proteome for Glycolysis (NES −1.11 vs. +1.40) and Hypoxia (NES −1.89, P adj < 0.001 vs. +1.34, ns), although proteomic enrichment did not reach FDR significance. Phosphoproteomic analysis revealed enzyme-specific rather than pathway-wide changes: HK1 (log2FC + 0.18, FDR < 10 −5 ) and PGAM1 (+0.40, FDR = 0.02) showed increased phosphorylation, whereas ALDOA, LDHB, PKM, and PFKM showed decreased phosphorylation (all FDR < 0.01). Conclusions Our study identifies a transcript-protein disconnect in glycolytic metabolism in human HCM. HIF1-associated transcriptional programs were reduced rather than activated. Oxidative pathways (OXPHOS, TCA cycle, FAO) showed coordinated downregulation across RNA and protein levels, whereas glycolysis exhibited frequent RNA-protein divergence, suggesting distinct regulatory mechanisms across metabolic pathways in HCM.