GROWTH differentiation factor 15 (GDF15) may protect against alcohol-associated liver disease (ALD) by suppressing neutrophil metabolism and inflammatory activity, according to new research published in Gut. The findings identify a previously underexplored mechanism through which hepatocytes regulate immune responses and highlight GDF15 as a potential therapeutic target for alcohol-related liver injury.
Researchers investigated the role of GDF15 in hepatocyte–neutrophil interactions using human samples, experimental mouse models, transcriptomic profiling, and metabolic assays.
GDF15 expression was predominantly localised to hepatocytes and was elevated in both patients with ALD and experimental mouse models. This increase was dependent on endoplasmic reticulum stress, suggesting a link between hepatocyte injury and GDF15 production.
Genetic deletion of hepatic GDF15 exacerbated ALD in mice, whereas hepatic overexpression or administration of recombinant GDF15 reduced disease severity. These protective effects were accompanied by changes in hepatic neutrophil accumulation and function.
Further analysis revealed that GDF15 limited neutrophil recruitment and activation through signalling involving an activin receptor-like kinase 5 (ALK-5) and transforming growth factor-β receptor II (TGF-βRII) heterodimer.
GDF15 also reduced neutrophil glycolytic metabolism and the formation of neutrophil extracellular traps (NETs), structures implicated in inflammatory responses.
By suppressing NET formation, GDF15 weakened NET-induced metabolic reprogramming of macrophages, resulting in reduced inflammatory cytokine release.
Together, these mechanisms alleviated ethanol-induced hepatic steatosis, inflammation, and liver injury in experimental models.
To investigate the therapeutic relevance of these findings, researchers pharmacologically targeted NETs in mice with hepatocyte-specific GDF15 deficiency.
This intervention alleviated the worsening of ALD associated with GDF15 deletion, improving hepatic steatosis, inflammation, and liver injury.
The findings suggest that hepatocyte-derived GDF15 acts as a negative regulator of harmful interactions between neutrophils and macrophages during ALD progression.
Although the protective effects were demonstrated experimentally, the study provides a mechanistic basis for investigating GDF15 signalling and neutrophil metabolism as potential therapeutic strategies. Further research is needed to determine whether these findings can be translated into effective treatments for patients with ALD.
Reference
Li X et al. Growth differentiation factor 15 ameliorates alcohol-associated liver disease by diminishing the glycolytic metabolism of neutrophils. Gut. 2026;DOI:10.1136/gutjnl-2026-339970.
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