Thymosin α1 improves the outcomes of patients with hepatitis B virus-related acute-on-chronic liver failure by restoring immune balance.

BACKGROUND: Thymosin α1 (Tα1) has been shown to improve survival in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF), but its immunomodulatory mechanisms remain unclear. This study investigated how Tα1 restores immune homeostasis to confer a survival benefit in these patients. METHODS: In this open-label, randomized controlled trial (NCT03082885), 73 patients with HBV-ACLF received either standard medical therapy (SMT, n = 38) or SMT plus Tα1 (n = 35). Peripheral blood immune cell subsets were analyzed by flow cytometry and serum cytokine levels were measured by ELISA. Patients were stratified by 90-day transplant-free survival. RESULTS: Patients who survived at 90 days exhibited a higher proportion of effector T (TE) cells and lower levels of regulatory T cells (Tregs) at baseline compared to non-survivors. Survivors also had significantly higher initial levels of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ) and lower levels of TGF-β. Over time, survivors showed a gradual decline in inflammatory markers, whereas non-survivors developed a progressive inflammatory storm. Tα1 treatment significantly increased 90-day transplant-free survival and was associated with reduced frequencies of Tregs and CD226Treg subsets at weeks 4-8. Tα1 also moderated the late-stage hyperinflammatory response without compromising early immune activation. CONCLUSIONS: Tα1 improves clinical outcomes in HBV-ACLF by rebalancing the immune response-mitigating excessive inflammation and preventing immune paralysis by modulating T-cell differentiation and cytokine production, thereby breaking the cycle of hyperinflammation and immunosuppression that characterizes ACLF progression.