Pumilio2 deficiency promotes iron-dependent macrophage inflammation via TfR1 upregulation in lupus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by persistent pathogenic IgG deposition, inflammation, and progressive organ damage. Despite its clinical importance, the mechanisms underlying sustained IgG-induced inflammation remain poorly understood, posing a major challenge for effective therapeutic intervention. Here, we identify Pumilio2 (Pum2), a post-transcriptional RNA-binding protein, as a crucial negative regulator of IgG-induced inflammation in lupus. Pum2 is consistently downregulated in SLE patient tissues and lupus-prone MRL/lpr mice. Using Pum2-deficient mice and MRL/lpr mice carrying Pum2 mutations generated via backcrossing, we demonstrate that Pum2 deficiency amplifies IgG-triggered immune activation, leading to aggravated tissue injury and accelerated disease progression. Mechanistically, loss of Pum2 in macrophages upregulates transferrin receptor 1 (TfR1), resulting in intracellular iron overload and enhanced proinflammatory responses upon IgG stimulation. Pharmacological inhibition of iron uptake or chelation effectively suppresses this inflammatory phenotype, revealing a functional Pum2-TfR1-iron axis linking RNA-level regulation to immune activation. Our findings establish Pum2 as a previously unrecognized checkpoint connecting post-transcriptional regulation, iron metabolism, and innate immunity in SLE. Targeting this pathway may offer a novel therapeutic strategy for mitigating persistent IgG-driven inflammation in lupus and related autoimmune diseases.