Abstract

Prosthetic wear particle-driven macrophage inflammation severely limits the long-term efficacy of total joint replacements by causing aseptic loosening. However, the specific mechanisms by which wear particles induce macrophage inflammation remain incompletely elucidated. Itaconic acid produced by the Krebs cycle is markedly up-regulated in TiPs-stimulated macrophages, which may modulate mitochondrial metabolism through protein itaconation or competitive inhibition. Here, using 4-OI, we demonstrate that itaconate functions as an endogenous metabolic regulator that suppresses SDH activity, thereby significantly inhibiting STING pathway activation. Moreover, 4-OI can alkylate STAT1, preventing its phosphorylation and relieving transcriptional repression of the mitochondrial transcription factor TFAM, which stabilizes mitochondrial homeostasis and attenuates macrophage inflammation. In a murine calvarial osteolysis model, 4-OI reversed bone destruction induced by TiPs and TFAM knockdown. Collectively, our findings establish itaconate as a critical endogenous metabolite that alleviates wear particle–mediated inflammation and osteolysis by reprogramming macrophage metabolism.