Regulated cell death in autoimmune diseases: molecular mechanisms and therapeutic opportunities

Autoimmune diseases develop from a breakdown in immune tolerance and arise through complex interactions among genetic susceptibility, environmental factors, immune dysregulation, and tissue damage. Although apoptosis has traditionally been recognized as a central mechanism for maintaining immune homeostasis, increasing evidence has identified several non-classical forms of regulated cell death (RCD) that also contribute to autoimmune disease pathogenesis. These pathways include ferroptosis, pyroptosis, necroptosis, PANoptosis, NETosis, parthanatos, and cuproptosis. Unlike classical apoptosis, many of these RCD mechanisms are strongly pro-inflammatory and promote the release of damage-associated molecular patterns (DAMPs), cytokines, oxidized lipids, and autoantigens, thereby enhancing both innate and adaptive immune responses. Recent studies indicate that dysregulation of RCD pathways contributes to chronic inflammation, impaired self-tolerance, immune cell abnormalities, and progressive tissue injury in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, multiple sclerosis, sjögren's syndrome, systemic sclerosis, type 1 diabetes, ulcerative colitis, dermatomyositis, ankylosing spondylitis, Chronic Dermatitis, antiphospholipid syndrome, Nephritis, and ANCA-associated vasculitis. These pathways do not function independently but form an interconnected network with extensive molecular crosstalk and compensatory interactions that influence disease progression. This review highlights the molecular mechanisms underlying emerging RCD pathways, their cell-specific roles in autoimmune diseases, and the evidence linking their involvement to disease initiation and progression. Furthermore, it discusses current and potential therapeutic approaches targeting major regulators of ferroptosis, pyroptosis, necroptosis, PANoptosis, NETosis, cuproptosis, and parthanatos. Improved understanding of the integrated landscape of the RCD network may facilitate the discovery of novel biomarkers and support the development of innovative therapies to restore immune tolerance and control chronic inflammatory damage in autoimmune diseases.