RIPK3 Orchestrates Scar-Associated Macrophage Dysfunction to Drive Pulmonary Fibrosis.

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant tissue remodeling and immune dysregulation. While receptor-interacting protein kinase 3 (RIPK3) is canonically recognized as a central executioner of necroptosis, its non-necroptotic functions in fibrosis remain unclear. Here, we identify a distinct, necroptosis-independent immunometabolic function of RIPK3 in regulating pulmonary fibrosis. Significant upregulation of RIPK3 was found in IPF patients and mice and was particularly enriched in macrophages. Subsequently, macrophage-specific RIPK3 knockout mice were established, which demonstrated resistance to bleomycin-induced fibrosis. Single-cell RNA sequencing further revealed that RIPK3 exerts its pro-fibrotic effects by controlling the functional state of a specific subset of scar-associated macrophages (SAMs). In vitro differentiation and functional analysis of SAMs from bone marrow-derived monocytes confirmed Spp1, Arg1, and Cx3cr1 as signature markers. Mechanistically, RIPK3 deficiency in SAMs inhibited the TGF-β-driven conversion of arginine to polyamines via the AKT-mTOR pathway, thereby suppressing polyamine accumulation and its pro-fibrotic effects. The translational potential of this finding was validated, as lung-specific Ripk3 knockdown also attenuated lung fibrosis. Our findings extend RIPK3 biology beyond its classical role in cell death, highlighting RIPK3 as a key metabolic regulator of the fibrotic niche and suggesting that targeting this immunometabolic axis represents a promising therapeutic strategy for IPF.