Hepatic ACSL4 Loss Boosts Endogenous Gamma-Glutamylcysteine to Alleviate Alcoholic Liver Disease

ablation mitigated key pathological manifestations in Gao-Binge model mice, as evidenced by reduced inflammatory cell infiltration and attenuated lipid accumulation. Mechanistically, ACSL4 inhibition augmented cellular antioxidant defence through elevating gamma-glutamylcysteine (γ-GC) levels. In addition, γ-GC bound to and suppressed the expression of protein tyrosine phosphatase type IVA member 1 (PTP4A1). Both genetic silencing and pharmacological inhibition of PTP4A1 attenuated the activation of the downstream MAPK-NF-κB inflammatory cascade. Dronedarone, identified as a novel compound targeting ACSL4, demonstrated efficacy in ameliorating the progression of ALD. Overall, these findings elucidate a novel mechanism wherein ACSL4 modulates antioxidant responses via a small bioactive peptide, highlighting ACSL4 as a potential therapeutic target for ALD.