Functional reprogramming of the hepatokine network: dynamic signaling shifts driving MASLD disease progression

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) exhibits a dynamic clinical progression, ranging from simple steatosis to MASH/fibrosis and hepatocellular carcinoma. The hepatokine network, composed of liver-secreted signaling proteins, is a key mediator of liver-centered interorgan crosstalk. However, interpreting hepatokines mainly as static protective or pathogenic biomarkers fails to fully explain why identical molecular signals may exert divergent biological effects across evolving pathological stages. Main body This review proposes a dynamic, signaling-oriented framework termed functional reprogramming. Rather than remaining fixed, the hepatokine network undergoes adaptive and maladaptive remodeling driven by the evolving hepatic microenvironment. We organize this process into three mechanism-based phases. First, the lipid accumulation phase (MASL) is characterized by early metabolic stress, compensatory induction of fibroblast growth factor 21 (FGF21) coupled with target-tissue hyporesponsiveness, and the upregulation of deleterious hepatokines. Second, the inflammatory/pro-fibrotic hijacking phase (MASH/fibrosis/cirrhosis) is marked by disrupted hepatic spatial zonation, inflammatory amplification mediated by leukocyte cell-derived chemotaxin 2 (LECT2) and follistatin (FST), and a transforming growth factor-beta 1 (TGF-β1)-centered pro-fibrotic signaling cascade. Third, the tumor-stage functional inversion phase (HCC) is characterized by context-dependent functional reversal, whereby fibrosis-associated mediators such as LECT2 may acquire tumor-suppressive roles, whereas traditionally protective factors such as FGF21 may undergo immune and metabolic rewiring. Conclusion The functional reprogramming model provides a mechanistic framework for interpreting MASLD disease progression and underscores the limitations of conventional single-target therapeutic strategies. Future interventions must shift from isolated target suppression toward stage-specific restoration of hepatokine network homeostasis.