BACKGROUND: Mixed lineage kinase domain-like protein (MLKL) serves as a critical mediator in necroptosis, a form of regulated cell death linked to various liver diseases. This study aims to specifically investigate the role of MLKL's adenosine triphosphate (ATP)-binding pocket in facilitating necroptosis-independent pathways that may contribute to liver disease progression. By focusing on this mechanism, we seek to identify potential therapeutic targets that can modulate MLKL activity, offering new strategies for the prevention and treatment of liver-related pathologies. AIM: To investigate the possibility of using the ATP-binding pocket-associated, necroptosis-independent MLKL pathway as a target for liver diseases. METHODS: Cell death following necroptosis stimuli was evaluated using cell proliferation assays, flow cytometry, and electron microscopy in various cells. The human liver organoid system was used to evaluate whether the MLKL ATP pocket-binding inhibitor could attenuate inflammation. Additionally, alcoholic and non-alcoholic fatty liver diseases animal models were used to determine whether MLKL ATP pocket inhibitors could attenuate liver injury. RESULTS: While an MLKL ATP pocket-binding inhibitor did not prevent necroptosis-induced cell death in RAW 264.7 cells, it did reduce the necroptosis-led expression of CONCLUSION: MLKL ATP pocket-binding inhibitor exerted anti-inflammatory effects through the necroptosis-independent MLKL pathway in an animal model of alcoholic liver disease.