Single-nucleus profiling reveals hepatocyte identity and immune features associated with corticosteroid response in severe alcohol-related hepatitis
(2026) Journal of Hepatology — (2026)
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Van Melkebeke, Lukas 
Boesch, Markus Ostyn, Tessa - et. al.
- Abstract
- Background & Aims: Severe alcohol-related hepatitis (sAH) is associated with high shortterm mortality. However, 30–40% of patients fail to respond to corticosteroids, the only proven pharmacological treatment. The pathophysiological mechanisms underlying sAH and the marked heterogeneity in treatment response remain incompletely understood. We aimed to define cellular changes associated with corticosteroid response in sAH and to identify baseline markers predictive of treatment outcome. Methods: Single-nucleus RNA sequencing was performed on liver biopsies from patients with biopsy-proven sAH (n=17), including paired baseline and day 8 biopsies in a subset (n=8). Patients were classified as corticosteroid responders (sAH-R; Lille score <0.45) or nonresponders (sAH-NR; Lille score ≥0.45). Liver biopsies from patients with acute decompensation of alcohol-related liver disease (AD; n=5) and healthy controls (n=4) were included for comparison. Findings were validated using immunohistochemistry and spatial proteomics in a large multicenter validation cohort (n=172). Results: At baseline, sAH-R patients exhibited a significantly higher proportion of liverinfiltrating S100A8+ monocytes compared to sAH-NR, a difference that persisted at day 8. sAH livers showed a marked reduction in mature hepatocytes and an expansion of stressed and intermediate hepatocyte populations compared to AD and healthy liver, indicating progressive loss of mature hepatocyte identity. This loss was more pronounced in sAH-NR patients, who also exhibited fewer cycling hepatocytes at day 8, consistent with impaired regenerative capacity. Expression of SULT2A1, a marker of mature hepatocyte identity, was significantly reduced in sAH-NR at baseline. Finally, liver biopsies with ≥50% SULT2A1-positive hepatocytes at baseline were strongly predictive of corticosteroid response. Conclusions: This study delineates distinct immune and hepatocyte changes associated with corticosteroid response in sAH. Baseline SULT2A1 expression may facilitate stratified treatment approaches in sAH.
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Citations
Van Melkebeke, L., Boesch, M., Ostyn, T., Huang, W., Akkaya, C., Van Sligtenhorst, M., El Abyad, D., Safaeifard, F., Dumarey, A., Wallays, M., Boeckx, B., Feio-Azevedo, R., Smets, L., Gustot, T., Trepo, E., Moreno, C., Putignano, A., Lasser, L., Colle, I., et al. (2026). Single-nucleus profiling reveals hepatocyte identity and immune features associated with corticosteroid response in severe alcohol-related hepatitis. Journal of Hepatology. Published. https://doi.org/10.1016/j.jhep.2026.04.002 (Original work published 2026)