Targeting mixed lineage kinase domain-like protein's non-necroptosis role: A new horizon in anti-inflammatory therapy for alcoholic liver disease.

Although mixed lineage kinase domain-like protein (MLKL) is widely recognized as a critical effector in the necroptotic signaling pathway, MLKL plays broader regulatory roles beyond programmed necroptosis. Notably, Xuan Yuan et al demonstrated that CPD4, an ATP-binding pocket inhibitor of MLKL, significantly reduces liver inflammation and improves liver function by inhibiting NF-κB signaling, suggesting its use as a potential therapeutic candidate for alcoholic liver disease. However, the pharmacokinetic properties and long-term toxicity of CPD4 require further evaluation. Moreover, a single therapeutic strategy targeting MLKL may not be sufficient. Future studies should focus on the precise regulation of MLKL and develop combination therapies to achieve dual intervention of inflammatory and cell death pathways. This paper provides an important theoretical foundation for translational research on MLKL-targeted therapy. However, its clinical translation requires overcoming existing limitations and further elucidating the regulatory network of MLKL in complex microenvironments.