Systems genetics analysis in genetically diverse mice identified hepatocyte growth factor activator (HGFAC) as a liver-secreted protein that influences cardiac gene expression programs. Cross-species validation in human datasets confirmed this liver-heart communication axis exists across species and appears linked to heart failure development. This discovery illuminates a previously unknown endocrine pathway connecting liver health to cardiovascular function. The finding carries significant implications for understanding why liver disease patients frequently develop heart problems. HGFAC could represent a novel therapeutic target for preventing heart failure in liver disease patients, or conversely, protecting liver function to maintain cardiovascular health. The research also supports emerging evidence that organ-to-organ communication networks critically regulate aging and disease susceptibility. However, this preprint awaits peer review, and the mechanistic details of how HGFAC influences cardiac function remain unclear. The mouse-to-human translation, while promising, requires validation in clinical populations. This appears to be incremental but important progress in mapping the complex endocrine networks that coordinate multi-organ health during aging.