RPS20 phosphorylation acts as a molecular switch to integrate inflammatory and oxidative stress signals in sepsis.

Sepsis is a life-threatening condition driven by dysregulated inflammation and oxidative stress, yet the role of ribosomal proteins in integrating these pathological signals remains poorly understood. Here, we identify ribosomal protein S20 (RPS20) as a phosphorylation-dependent switch coordinating inflammatory and oxidative stress responses in macrophages during sepsis. Proteomic analysis reveals thioredoxin (TXN) as the most dynamically altered RPS20 interactor upon LPS stimulation, with rapid complex dissociation and TXN nuclear translocation. Mechanistically, LPS-activated ERK1 directly phosphorylates RPS20 at T9 and S93. A phospho-ablative RPS20 mutant enhances RPS20-TXN binding, suppresses NLRP3 inflammasome activation, reduces ROS production, and attenuates pro-inflammatory cytokine secretion. Although RPS20 dephosphorylation does not affect NF-κB nuclear translocation, it selectively impairs p65 binding to specific gene promoters. In vivo, phosphorylation-deficient RPS20 ameliorates lung injury in septic mice. Collectively, RPS20 phosphorylation integrates inflammatory and oxidative signals, positioning RPS20 as a potential therapeutic target for sepsis.