Chemokine Signaling Shapes Hepatic Lipid Homeostasis through the CXCL12/CXCR4/CXCR7 Axis

The CXCL12/CXCR4/CXCR7 signaling axis, long recognized for its roles in cancer, fibrosis, and tissue repair, is emerging as a broader regulator of tissue homeostasis. Here, we uncover a previously unappreciated function of this pathway in regulating hepatic metabolism. We show that Cxcl12, Cxcr4, and Ackr3 (encoding CXCR7) are dynamically regulated during the fasting-refeeding transition and become dysregulated under conditions of diet-induced insulin resistance. Hepatocyte-specific depletion of Cxcl12 or overexpression of Ackr3 each led to hepatic triglyceride accumulation, indicating that balanced activity within this chemokine axis is essential for lipid homeostasis. Mechanistically, CXCR7 acts within hepatocytes to promote lipid storage and modulate insulin responsiveness by influencing mTORC1 signaling. In Ackr3overexpressing hepatocytes, mTORC1 activity was elevated under basal conditions but suppressed following lipid loading, reflecting a biphasic relationship between mTORC1 signaling and hepatic steatosis. In contrast, Cxcr4 overexpression had no significant metabolic impact, suggesting a nonredundant, hepatocyte-autonomous role for CXCR7. These findings establish a mechanistic link between chemokine signaling and nutrient sensing, positioning CXCR7 as a key modulator of hepatic energy metabolism. Analysis of human liver transcriptomic datasets revealed reduced CXCL12 and elevated CXCR4 and ACKR3 expression in NAFLD and NASH, supporting the translational relevance of this pathway. Together, our results identify the CXCL12/CXCR4/CXCR7 axis as an integral regulator of hepatic lipid balance and highlight CXCR7 as a potential therapeutic target for metabolic liver disease.