Integrated transcriptomic and proteomic analysis reveals ECM disruption and ALDH1L1-linked metabolic remodeling in klotho-deficient post-infarction heart failure.

BACKGROUND: The role of Klotho in heart failure (HF) and its underlying metabolic mechanisms remain unclear. This study investigated how Klotho deficiency affects extracellular matrix (ECM) homeostasis and metabolic regulation in post-myocardial infarction HF (MI-HF), with a focus on aldehyde dehydrogenase 1 family member L1 (ALDH1L1). METHODS: Wild-type (WT), Klotho haploinsufficient (Klotho+/-), MI-HF, and Klotho+/--MI-HF mouse models were used. Transcriptomic and proteomic analyses were performed. RESULTS: Compared with WT, Klotho+/- mice showed 84 differentially expressed genes (DEGs) and 311 differentially expressed proteins (DEPs) enriched in ECM-related pathways. MI-HF mice exhibited similar ECM enrichment. Importantly, comparison between Klotho+/--MI-HF and MI-HF identified 201 DEPs. Proteomic KEGG enrichment analysis revealed significant enrichment of ALDH1L1-related one‑carbon metabolism and NADPH regeneration pathways, along with significant downregulation of ALDH1L1 in Klotho-deficient HF mic. CONCLUSION: Klotho deficiency is associated with exacerbated post-myocardial infarction heart failure, accompanied by significant alterations in ECM homeostasis-related molecules and ALDH1L1-mediated one‑carbon metabolism and NADPH regeneration pathways. These findings suggest that the Klotho/ALDH1L1 axis may represent a potential therapeutic target for post-myocardial infarction heart failure.