Unveiling the nexus: Decoding interactions between regulated cell death and systemic lupus erythematosus pathogenesis for innovative therapeutic avenues

Systemic lupus erythematosus (SLE) is characterized by disruptions in cell death pathways and impaired clearance of apoptotic cells, resulting in immune dysregulation and tissue damage. This review explores the complex interplay of regulated cell death (RCD) mechanisms, including apoptosis, necroptosis, pyroptosis, NETosis, autophagy, and ferroptosis, in the pathogenesis of SLE. These pathways release autoantigens and danger signals, triggering autoimmune reactions and inflammation. Six various RCDs have mutual associates to support immune dysregulation and are associated with SLE. Apoptosis intrinsically induces immune tolerance by packaging dying cells into immunologically inert fragments. Deficiencies in apoptotic clearance will result in impaired tolerance. Necroptosis, pyroptosis, NETosis, and ferroptosis lead to cell membrane destruction, production of intracellular immunostimulatory components, and triggering a strong inflammatory immune reaction. Abnormal autophagic activity affects the development, differentiation, function, and metabolism of many immune cell subpopulations. Investigating the interconnections between cell death pathways and SLE sheds light on the disease's underlying mechanisms and provides opportunities for novel therapeutic interventions. The convergence of precision medicine and innovative strategies targeting these intricate pathways holds promise for expanding the landscape of SLE treatment. Multidimensional RCD interactions and therapeutic interventions in SLE: The graphical abstract illustrates the convergence of various regulated cell death (RCD) pathways-apoptosis, necroptosis, pyroptosis, NETosis, autophagy, and ferroptosis-in the pathogenesis of systemic lupus erythematosus (SLE). It highlights key molecular targets within these pathways and their linkage to inflammatory and autoimmune responses.Key points image Several regulated cell death products initiate activation of autoreactive B cells, leading to the formation of autoantibodies. Apoptotic disturbances and abnormal clearance of apoptotic cells enhance immune recognition of modified autoantigens. PANoptosis combines pyroptosis, apoptosis, and necroptosis, linking regulated cell death to lupus pathogenesis and inflammation.