c-Fos in immune regulation and inflammatory signaling: mechanisms and therapeutic implications

As the inducible component of the activator protein-1 (AP-1) transcription factor complex, c-Fos acts as a critical hub translating extracellular immune stimuli into context-specific transcriptional programs. This review outlines the mechanistic roles of c-Fos/AP-1 in immune regulation and inflammatory diseases, from inflammatory activation and regulation to tissue remodeling. We dissect how diverse upstream signals—including TLR4, TCR, FcϵRI, and RANK—converge on MAPK cascades (ERK1/2, JNK, and p38), and how cytokines like IL-6 engage JAK-STAT signaling to regulate c-Fos expression in a context-dependent manner. Following induction, c-Fos-containing AP-1 complexes form through heterodimerization with Jun family proteins and cooperate with NF-κB and NFAT to regulate pro-inflammatory cytokine production, osteoclastogenesis, tissue injury, and other cell-specific transcriptional programs. Furthermore, we discuss emerging evidence on c-Fos-mediated regulatory mechanisms that shape the magnitude and duration of inflammation across different cellular contexts. Finally, we evaluate current therapeutic strategies targeting the c-Fos/AP-1 axis, using the small-molecule inhibitor T-5224 as a case study, and address the challenges of cell-type-specific functions. We propose that selectively targeting pathological c-Fos/AP-1 activity while preserving physiological functions holds promise for precision immunomodulation in inflammatory disorders.