RESUMO
Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.
Assuntos
Artrite Experimental/prevenção & controle , Artrite Reumatoide/prevenção & controle , Ferroptose/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Imidazóis/farmacologia , Cetonas/farmacologia , Piperazinas/farmacologia , Inibidores do Fator de Necrose Tumoral/farmacologia , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Quimioterapia Combinada , Etanercepte/farmacologia , Etanercepte/uso terapêutico , Fibroblastos/citologia , Fibroblastos/metabolismo , Glutationa/metabolismo , Humanos , Imidazóis/uso terapêutico , Cetonas/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Piperazinas/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Membrana Sinovial/citologia , Inibidores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
This prospective nonrandomized, multicenter clinical trial was performed to investigate the efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 mo in the TACE + 131I-metuximab group (n = 160) and 3 mo in the TACE group (n = 160) (hazard ratio, 0.55; 95% CI, 0.43-0.70; P < 0.001). The median overall survival was 28 mo in the TACE + 131I-metuximab group and 19 mo in the TACE group (hazard ratio, 0.62; 95% CI, 0.47-0.82; P = 0.001). Conclusion: TACE + 131I-metuximab showed a greater antirecurrence benefit, significantly improved the 5-y survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.