Abstract Body (Do not enter title and authors here): Background: Interorgan communication is essential for coordinating organ functions, maintaining homeostasis, and adapting to disease. Although the liver and heart engage in multifaceted interactions, the mechanisms mediating liver-to-heart communication in heart failure (HF) remain largely unexplored, and the hepatic regulatory factors that modulate cardiac responses in HF have yet to be clearly defined. Therefore, this study aimed to explore the involvement of hepatic regulatory factors in HF and to evaluate their functional roles.

Methods: To investigate molecular changes in the liver during HF, RNA-sequencing analysis was performed on liver tissues from HF mouse models induced by angiotensin II (Ang II) infusion. To assess the functional role of hepatocyte-derived CXCL1 in HF, liver-specific knockdown was achieved using an adeno-associated virus serotype 8 (AAV8) vector encoding shRNA targeting CXCL1 (shAAV-CXCL1).

Results: After RNA-sequencing analysis, we identified 2,218 differentially expressed genes (DEGs) in the liver of Ang II-infused mice compared to saline-infused controls, including 1,915 upregulated and 303 downregulated genes (|fold change| ≥ 2, P < 0.05). These DEGs were associated with multiple HF-related pathophysiological pathways. Notably, CXCL1 was selected for further investigation based on its potential role in the inflammatory response, and subsequent validation confirmed a marked increase in hepatic CXCL1 expression in Ang II-induced HF mice. We then examined its potential role in HF by intravenously administering shAAV-CXCL1, which preferentially accumulated in the liver (P < 0.05) and significantly reduced hepatic CXCL1 expression. Consequently, the inhibition of hepatocyte-derived CXCL1 markedly attenuated Ang II-induced cardiac dysfunction, myocardial fibrosis, and hypertrophy (P < 0.05), without inducing systemic toxicity.

Conclusion: Our findings suggest that hepatic CXCL1 contributes to cardiac dysfunction in HF, highlighting its potential as a therapeutic target.