Candidate Biomarkers Shared by MASLD and Heart Failure Reveal Organ-Specific Expression Patterns in Experimental HFpEF

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly termed non-alcoholic fatty liver disease, NAFLD) and heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF), frequently coexist and share metabolic and inflammatory disorders. However, whether this comorbidity is characterized by a cross-organ molecular signature between the liver and heart remains unclear. Methods: We employed a two-stage discovery–validation strategy. Public hepatic datasets from MASLD and generalized HF (predominantly end-stage/HFrEF) were independently analyzed. Differentially expressed genes (DEGs) in both conditions were identified and classified as candidates. Candidates were prioritized based on functional enrichment, immune-cell deconvolution, ROC performance, and their localization in cardiac single-cell transcriptomes. Subsequently, the cross-organ signature was evaluated in cardiac and hepatic tissues from an experimental HFpEF mouse model. Results: We identified 1104 HF-associated and 348 MASLD-associated DEGs with 28 overlapping genes. Among these, EGR1 and PHLDA1 constituted the significant discordant cross-organ signature, showing an increased expression in HF cardiac datasets but decreased expression in MASLD hepatic datasets. Cardiac single-cell analysis indicated that the candidate signal was predominantly enriched in fibroblasts. Following the successful establishment of an HFpEF mouse model, this opposite-direction expression pattern was validated across organs: EGR1 and PHLDA1 were upregulated in the heart but downregulated in the liver. Conclusions: Through transcriptomic discovery and experimental validation, we identified an opposite cross-organ molecular signature characterized by EGR1 and PHLDA1. These genes represent candidate biomarkers of heart–liver remodeling. Further cell-specific and functional studies are required to determine whether EGR1 and PHLDA1 are merely biomarkers of organ-specific remodeling or actively contribute to inter-organ communication.