The CCAAT/enhancer binding protein β (C/EBPβ) is a key transcription factor regulating immune homeostasis. Although its oncogenic roles are well-established, its context-dependent functions in autoimmune diseases, which affect 5–10% of the global population, remain incompletely understood. This review aims to synthesize current knowledge on C/EBPβ’s paradoxical roles in autoimmunity and evaluate its emerging therapeutic potential. We detail how C/EBPβ, through its antagonistic isoforms LAP*/LAP (activator) and LIP (repressor), operates as both a pathogenic driver and a protective regulator in a cell-type-specific manner across major autoimmune conditions. In rheumatoid arthritis, it coordinates synovitis, cartilage degradation, and bone erosion. In lupus nephritis, it promotes podocyte pyroptosis. In multiple sclerosis, it drives pathogenic Th17 differentiation and microglial activation. Conversely, in ulcerative colitis, it can also facilitate anti-inflammatory M2 macrophage polarization. Critically, we evaluate emerging strategies to target this transcription factor, including isoform-selective inhibitors and peptide-based degraders, which challenge its historical classification as “undruggable” and open novel therapeutic avenues. C/EBPβ emerges as a pivotal, context-dependent orchestrator of autoimmune pathogenesis. Understanding its isoform-specific functions provides a framework for precision medicine. Future research should focus on mapping isoform dynamics in patient tissues and developing targeted therapies, positioning C/EBPβ as a promising and translational therapeutic target for autoimmune diseases.
Wang et al. (2026) studied this question.