Hepatokines and stellakines in liver and neurological diseases: The liver-brain axis.

Interorgan communication is essential for maintaining homeostasis. Numerous mediators, including cytokines and adipokines, have been identified, and their roles in interorgan crosstalk have been clarified. In particular, interactions between peripheral organs and the central nervous system (CNS), such as the liver-brain axis, have become a major focus for identifying therapeutic targets for disease. Among the various secreted mediating factors, such as hepatokines and stellakines, are released from hepatocytes and hepatic stellate cells, respectively in response to diverse stimuli, and they contribute to hepatic inflammation, fibrosis, and tissue injury and repair. Under pathological conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), aberrantly expressed hepatokines and stellakines can enter the bloodstream and the brain parenchyma via disrupted blood-brain barrier (BBB). These factors can lead to BBB impairment or recovery, modulate peripheral immune cell infiltration, and either exacerbate or attenuate neuroinflammation, thereby influencing the development and suppression of neurological diseases. They may also aggravate or alleviate neuropsychiatric symptoms. Accordingly, therapeutic modulation of hepatokines or stellakines can have either detrimental or beneficial effects within the neural microenvironment. Collectively, although research on their roles in the liver-brain axis remains limited, elucidating their mechanisms of action may help identify novel preventive and therapeutic targets for neurological diseases.