Cold-induced liver dysfunction drives cardiac damage through a liver-heart axis.

A cold environment is a significant risk factor for cardiovascular diseases (CVDs), and its pathophysiological mechanisms involve complex interactions across multiple organ systems. However, the role of the liver as a central organ for metabolism and energy homeostasis in cold-related CVDs remains unclear. In this study, we systematically investigated the role of the liver in the pathogenesis of cardiac damage in cold regions by integrating clinical cohort studies, bioinformatic analysis, and animal experiments. The results demonstrated that in a cold-exposed population, serum alanine aminotransferase levels remained an independent risk factor for patients with heart failure after adjusting for traditional cardiovascular risk factors. Transcriptomic analysis of liver tissues from chronically cold-exposed mice in a public database revealed that differentially expressed genes were significantly enriched in pathways related to lipid metabolism and cell cycle regulation. Animal experiments further confirmed that long-term cold exposure induced liver injury and dyslipidemia, accompanied by cardiac structural remodeling and myocardial injury. We identified and validated an activated hepatic cell cycle program through protein-protein interaction network analysis and Ki67 immunohistochemistry staining in cold-exposed mice. In vitro co-culture experiments further demonstrated that hepatocytes overexpressing cell cycle regulators induce cardiomyocyte injury through paracrine secretion of multiple factors. In summary, we identified liver injury as an independent risk factor for CVDs in cold regions and demonstrated that chronic cold stress induces liver metabolic dysregulation and aberrant activation of cell cycle signaling, which together contribute to cardiac injury through liver-heart crosstalk.