TAK1 at the crossroads of multiple regulated cell death pathways: from molecular mechanisms to human diseases

Regulated cell death (RCD), the form of cell death that can be genetically controlled by multiple signaling pathways, plays an important role in organogenesis, tissue remodeling, and maintenance of organism homeostasis and is closely associated with various human diseases. Transforming growth factor‐beta‐activated kinase 1 (TAK1) is a member of the serine/threonine protein kinase family, which can respond to different internal and external stimuli and participate in inflammatory and immune responses. Emerging evidence suggests that TAK1 is an important regulator at the crossroad of multiple RCD pathways, including apoptosis, necroptosis, pyroptosis, and PANoptosis. The regulation of TAK1 affects disease progression through multiple signaling pathways, and therapeutic strategies targeting TAK1 have been proposed for inflammatory diseases, central nervous system diseases, and cancers. In this review, we provide an overview of the downstream signaling pathways regulated by TAK1 and its binding proteins. Their critical regulatory roles in different forms of cell death are also summarized. In addition, we discuss the potential of targeting TAK1 in the treatment of human diseases, with a specific focus on neurological disorders and cancer.