A Novel Perspective on the Pathogenesis of Arthritis From the PANoptosis Framework: From Cell Death Networks to Macrophage Immune Infiltration

Arthritis, particularly rheumatoid arthritis (RA) and osteoarthritis (OA), comprises a group of complex disorders characterized by chronic inflammation and progressive joint structural destruction. RA represents an autoimmune condition with robust synovial inflammation, whereas OA manifests mainly as low-grade degenerative inflammation. In recent years, the role of programmed cell death (PCD) in the pathogenesis of arthritis has attracted increasing attention; mechanistic evidence for PANoptosis is more abundant in RA, while its contribution in OA remains putative. However, traditional investigations focusing on single cell death pathways are insufficient to account for the persistence of inflammation and the complexity of cell fate decisions observed in arthritic conditions. PANoptosis, a recently defined integrated mode of cell death, is orchestrated by the PANoptosome complex, which coordinates apoptosis, necroptosis and pyroptosis. This conceptual framework provides a novel perspective for understanding the multidimensional pathological mechanisms underlying arthritis. In this review, we systematically delineate the core concepts and molecular basis of PANoptosis, and explore its crosstalk with necroptosis, pyroptosis, apoptosis, ferroptosis and autophagy within the arthritic microenvironment. Particular emphasis is placed on the pivotal role of macrophages as central executors of PANoptosis in mediating immune cell infiltration and amplifying inflammatory responses. Furthermore, we discuss emerging therapeutic strategies targeting PANoptosis-related pathways. By integrating the 'PANoptosis-immune infiltration-inflammatory feedback' axis, this work aims to provide a novel theoretical framework for elucidating disease mechanisms and advancing clinical interventions in arthritis. Furthermore, we summarize candidate PANoptosis-related biomarkers and discuss existing translational bottlenecks for their clinical deployment.