Alcohol-induced hepatic secretome identifies the FSTL3–activin A–ActRII axis as a therapeutic target in alcohol-related liver disease

Background Alcohol-related liver disease (ALD) is a leading cause of advanced liver disease yet has no effective medical therapies, making it unique among prevalent and morbid liver diseases. Objective We aimed to identify novel therapeutic targets for ALD by integrating human serum proteomics with the alcohol-induced hepatic secretome in mice. Design We analysed human serum proteomics and the alcohol-induced hepatic secretome across mouse models of ALD to identify candidate therapeutic targets which converged on follistatin-like 3 (FSTL3), an activin A antagonist. FSTL3 expression was characterised in mouse liver, human liver organoids and across the spectrum of human ALD. Single-cell and spatial transcriptomics were used to identify its cellular source. Its functional role was tested using hepatic FSTL3 overexpression and knockout mouse models, and the underlying mechanism was examined in cellular systems. Three clinical-stage therapeutics targeting different nodes of the activin A–ActRII pathway were evaluated in ALD: garetosmab (anti-activin A), sotatercept (ActRIIA-Fc) and bimagrumab (anti-ActRIIA/B). Results Integrative analysis identified FSTL3, a secreted TGF-β superfamily inhibitor not previously implicated in ALD. FSTL3 was induced by ethanol in mouse liver, human liver organoids and across the spectrum of human ALD, with activated hepatic stellate cells identified as its source. FSTL3 overexpression attenuated, whereas knockout aggravated the liver’s histological and transcriptional response to ethanol. Mechanistically, ethanol induced hepatocyte-autonomous secretion of activin A, which signalled through ActRII to induce p21, an axis neutralised by FSTL3. Garetosmab, sotatercept and bimagrumab each phenocopied FSTL3’s protective effect and prevented ethanol-dependent p21 induction. Conclusion The FSTL3–activin A–ActRII axis is a protective, druggable pathway in ALD, providing a rationale for repurposing existing clinical-stage therapeutics for a disease with no effective treatment.