Growth differentiation factor 15: from stress response to clinical utility in chronic liver diseases

TL;DR

GDF15 is a stress-related protein that shows promise as a noninvasive biomarker for chronic liver diseases, offering insights beyond traditional measures like fibrosis.

Contribution

The study highlights GDF15 as a novel, fibrosis-independent biomarker with potential for risk stratification and therapeutic targeting in chronic liver diseases.

Findings

Elevated GDF15 levels correlate with fibrosis severity, HCC risk, and mortality in chronic liver diseases.

GDF15 integrates hepatocellular and stromal stress pathways, capturing residual risk beyond fibrosis stage.

GDF15 has dual roles, acting both protectively and pathologically in liver disease progression.

Abstract

The clinical landscape of chronic liver disease has changed with effective antiviral therapies, enabling the eradication of hepatitis C virus and the durable suppression of hepatitis B virus replication. Despite these advances, patients remain at risk for hepatocellular carcinoma (HCC) and other liver-related complications, but the growing burden of metabolic dysfunction-associated steatotic liver disease (MASLD) has created new challenges for clinical practice. These trends emphasize the need for reliable, noninvasive biomarkers that can stratify risk and guide long-term management across diverse etiologies. Growth differentiation factor 15 (GDF15), a stress-inducible cytokine, has attracted increasing interest as a promising biomarker. Its expression is induced by metabolic, oxidative, and inflammatory stress, and circulating levels increase with disease progression. Elevated serum GDF15 is consistently associated with fibrosis severity, HCC risk, hepatic decompensation, and mortality. Importantly, GDF15 is not merely a surrogate of fibrosis; rather, it integrates hepatocellular and stromal stress pathways and captures residual risk beyond fibrosis stage, liver function scores, and conventional biomarkers. In addition to its prognostic association, GDF15 has diverse biological effects. It may act as a protective response by limiting inflammation and cellular injury; yet, in other contexts, it contributes to fibrogenesis, tumor progression, immunosuppression, and cachexia. These dual roles highlight both the potential and the complexity of targeting GDF15 in therapeutic strategies. Collectively, the results of the current study indicate that GDF15 represents a promising biomarker in chronic hepatic diseases and is clinically independent of hepatic fibrosis. Further work is needed to clarify the underlying mechanisms, validate the prognostic utility, and determine whether GDF15 can be developed as a therapeutic target within precision medicine approaches.

The online version contains supplementary material available at 10.1007/s00535-025-02336-7.

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