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.