Published online Apr 14, 2025. doi: 10.3748/wjg.v31.i14.104523
Revised: February 25, 2025
Accepted: March 13, 2025
Published online: April 14, 2025
Processing time: 108 Days and 22.1 Hours
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.
Core Tip: Mixed lineage kinase domain-like protein (MLKL) functions to mediate necroptosis, inhibit autophagy, and regulate inflammatory responses. The MLKL exhibits different functions in various types of liver cells, leading to diverse manifestations of different liver diseases. This complexity not only brings challenges in understanding the roles of MLKL in liver diseases, but also presents an obstacle in developing therapeutic strategies for targeting MLKL. Here, we briefly review the functions of MLKL and analyze its specific roles in different types of liver cells, aiming to provide clear strategies for precisely targeting MLKL in the treatment of liver diseases.