Mixed lineage kinase domain-like protein in liver diseases: Cell-type-specific functions and dual roles

In this letter, we comment on the article by Xuan Yuan et al, published in the recent issue of the World Journal of Gastroenterology. Mixed lineage kinase domain-like protein (MLKL) exhibits cell-type-specific functions in liver parenchymal and non-parenchymal cells, playing dual roles in the pathogenesis of liver diseases. In hepatocytes, MLKL primarily mediates necroptosis and inhibits autophagy, thereby exacerbating liver injury. Conversely, in non-parenchymal liver cells, MLKL modulates inflammatory responses and promotes fibrotic processes, thereby driving disease progression. Notably, MLKL also demonstrates protective functions under specific conditions. For instance, MLKL can inhibit intracellular bacterial replication, promote endosomal trafficking, and facilitate the generation and release of extracellular vesicles, potentially exerting hepatoprotective effects. Understanding these cell-type-specific mechanisms of MLKL action, including its dual roles in promoting injury and providing protection, is crucial for elucidating the complex pathogenesis of liver diseases and developing targeted therapeutic strategies.