RSK1-SRF signaling axis drives fibroblast activation and pulmonary fibrosis: Genetic causality and therapeutic targeting

Pulmonary fibrosis is driven by persistent fibroblast activation and extracellular matrix (ECM) accumulation, yet upstream regulators that initiate and sustain these programs remain incompletely defined. Here, we tested whether the ribosomal S6 kinase 1-serum response factor (RSK1-SRF) axis contributes to idiopathic pulmonary fibrosis (IPF) and represents a tractable therapeutic target. Mendelian randomization supported a causal association between RSK1 and IPF risk, which aligned with increased RSK1 activity in human IPF lungs and bleomycin-injured mice. In lung fibroblasts, pharmacologic RSK1 inhibition blunted TGF-β-induced fibroblast-to-myofibroblast transition and ECM production. Mechanistically, RSK1 associated with SRF and promoted SRF phosphorylation and activation, thereby enhancing SRF-dependent profibrotic transcription. In vivo, perturbation of the RSK1-SRF axis attenuated fibroblast activation, ECM deposition, and histologic fibrosis. Collectively, these findings indicate RSK1 as a druggable upstream driver of SRF-dependent profibrotic programs and motivate further evaluation of RSK1-directed strategies for IPF.