STAT1 itaconation prevents macrophage cytolistic mtDNA -induced inflammation in Wear Particle-Induced Aseptic Loosening

Abstract Prosthetic wear particle-driven macrophage inflammation severely limits the long-term efficacy of total joint replacements through aseptic loosening. However, the specific mechanisms by wear particles induce macrophage inflammation remain incompletely elucidated. Itaconic acid produced by the krebs cycles is markedly up-regulated in TiPs-stimulated macrophages, whcih may modulate mitochondrial metabolism via itaconation or competitive inhibition of specific proteins. Here, using the 4-octyl itaconate (4-OI, a derivative of itaconic acid), we demonstrate that itaconate functions as an endogenous metabolic regulator that suppresses succinate dehydrogenase (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.