Liver-spleen axis: Deciphering a crucial crosstalk in non-alcoholic fatty liver disease progression and therapeutic implications

Non-alcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic fatty liver disease, is a highly prevalent metabolic liver disorder, closely linked to obesity, insulin resistance, and chronic low-grade inflammation. While traditionally viewed through the liver-adipose-gut axes, emerging evidence identifies the liver-spleen axis as a critical pathway in disease progression. This review examines the anatomical and portal vascular connections that facilitate direct communication between these organs, focusing on how splenic immune reprogramming—specifically involving myeloid-derived suppressor cells, natural killer/natural killer T cells, and pro-inflammatory signaling—drives the transition from simple steatosis to advanced cirrhosis. We further explore the diagnostic utility of splenic volume, metabolic activity, and stiffness as non-invasive markers that correlate with the severity of hepatic fibrosis and portal hypertension. In conclusion, the spleen serves as a vital immunometabolic regulatory hub and a sentinel for hepatic stress. Recognizing this axis offers significant potential for precision diagnostics and novel therapeutic interventions. Future research should focus on longitudinal intervention trials and multi-omics studies to fully decode the signaling crosstalk within the NAFLD spectrum, shifting the management of the disease toward a more systemic, integrated approach.