Publications by Year: 2026

BACKGROUND: Increased circulating pro-inflammatory cytokine levels correlate with mortality in severe alcohol-associated hepatitis (AH), but their kinetics during disease progression or response to treatment remain unexplored.

OBJECTIVE: We longitudinally assessed circulating biomarkers in a severe AH cohort enrolled in a multicenter, double-blind clinical trial.

DESIGN: Eighty-nine patients with severe AH (MELD≥20) from 4 US sites were randomly assigned to treatment with IL-1receptor antagonist (IL-1Ra) + pentoxifylline + zinc (anakinra: 47) or methylprednisolone + placebo (steroid: 42). Plasma levels of 43 indicators of AH pathology (inflammation, bacterial translocation, liver regeneration, tissue remodeling, and cell-activation) were assessed on days 0, 7, 28, 90 and 180 after enrollment, and in 27 healthy controls.

RESULTS: Baseline characteristics and cytokine levels were similar between treatment groups but significantly different compared to healthy controls. Consistent with anakinra administration, day 7 IL-1Ra levels were significantly increased in the anakinra group accompanied by elevated levels of several other cytokines. IL-1β levels were increased in the steroid group on day 28. Strong correlations were observed between IL-1α and IL-17A as well as IL-1β and IL-13 both prior to and during treatment. Although the dysregulated biomarkers demonstrated improving trends in survivors, most did not normalize by day 180. Markers associated with 90-day mortality were distinct between the treatment groups with few exceptions (IL-13-absolute level; Sonic hedgehog and sTNFR-1-level change).

CONCLUSIONS: Circulating cytokine and immune biomarkers dynamically change in AH during treatment, disease progression and/or resolution. Our results highlight the importance of treatment-specific biomarkers in future clinical trials.

BACKGROUND: Cyclic GMP-AMP synthase (cGAS) catalyzes the production of cGAMP, which activates the STING-IRF3 signaling pathway. Previous investigations indicated a role for STING-IRF3 in early alcohol-associated liver disease (ALD). In this study, we examined the role of cGAS in liver damage and inflammation in early ALD.

METHODS: Wild-type (WT) or cGAS knockout (cGAS-KO) mice received a single dose of alcohol (5 g/kg), and in WT mice with or without a cGAS inhibitor, RU.521 (5 mg/kg) or 2'-3' cGAMP or control. Liver and serum were evaluated after 9 hours of alcohol administration.

RESULTS: Alcohol gavage in cGAS knockout (cGAS-KO) mice led to increased liver damage compared with WT mice. Inhibition of cGAS with the small molecule, RU.521, also resulted in increased serum alanine and aspartate aminotransferases. cGAS deficiency or inhibition made the liver susceptible to alcohol-induced apoptosis. Alcohol-fed cGAS-KO mice and WT mice treated with the cGAS inhibitor showed enhanced unfolded protein response in the liver. This was associated with elevated levels of the proinflammatory cytokines, macrophage migration inhibitory factor, CD68+ cells, Ly6G+ cells, and chemokines like lipocalin-2 and neutrophil elastase. Primary hepatocytes isolated from cGAS-KO mice displayed increased levels of cleaved caspase-3, XBP1s, and CHOP after alcohol administration as compared with WT control hepatocytes. Interestingly, restoration of cGAMP levels after cGAS inhibition improved liver damage and autophagic flux.

CONCLUSIONS: Our findings highlight that cGAS deficiency or cGAS inhibition predisposes the liver to increased damage, apoptosis, and unfolded protein response in early ALD. An increase in the proinflammatory cytokine MIF and chemokines involved in neutrophil recruitment might contribute to the increased liver damage. In summary, our findings indicate a protective role for cGAS activation in early ALD.