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Introduction Fibroblasts shift between immunosuppressive and inflammatory states and may be persistently altered by inflammatory stimuli, in a process known as trained immunity. Trained immunity is classically associated with innate/myeloid cells, interestingly, fibroblasts also exhibit memory-like responses. Examples include transcriptional and epigenetic modifications, enhanced functional response to subsequent stimuli and metabolic alterations, leading to negative pathological outcomes. Importantly, how trained immunity in lung fibroblasts influences lung fibrosis development and whether this process holds therapeutic promise, has not been addressed. The NFkB transcription factor cRel/REL orchestrates epigenetic and metabolic changes in immune cells, implicating this molecule as a putative regulator of trained immunity. We hypothesise that fibroblast-trained immunity, driven by release of pro-inflammatory cytokines, drives lung fibrosis.Material and Methods This research programme aims to determine how fibroblast trained immunity drives the pathogenesis of lung fibrosis and whether these pathways can be targeted therapeutically. This project will employ a multifaceted approach integrating transcriptomics, metabolomics, and spatial analysis to unravel the role of fibroblast trained immunity in lung fibrosis, focusing on translating findings into potential treatments.Results Our preliminary data show conditional myeloid cell deletion of cRel reduced fibrosis in mouse models, suggesting cRel/REL signalling is crucial for fibroblast-immune cell interactions in lung fibrosis. We have shown REL is constitutively active in SSc patient fibroblasts and is associated with a distinct transcriptional profile linked to fibrosis. Inhibiting REL with IT603 reduced fibrotic markers in human dermal fibroblasts. Furthermore, SSc-ILD myofibroblasts have elevated REL levels and expression in the lung is localised in immune cells and fibroblastic foci.Conclusions This may indicate that trained immunity in lung fibroblasts, driven by cRel/REL, may contribute to lung fibrosis, representing a potential therapeutic target.