Activating the iNOS regulatory pathway by arginine deprivation targets energy metabolism to induce autophagy-dependent apoptosis against spinal echinococcosis

• Published in: Biochemical pharmacology 2024-09, Vol.227, p.116453, Article 116453
• Main Authors: Abudouaini, Haimiti, Zhang, Xuefang, Dai, Yi, Meng, Yibin, Lu, Qing, Ren, Qian, Sun, Haohao, Ma, Yibo, He, Baorong, Wang, Sibo
• Format: Article
• Language: English
• Subjects: Agrimol B; Amino acid metabolism; Animals; Apoptosis - drug effects; Apoptosis - physiology; Arginine - metabolism; Arginine deprivation; Autophagy - drug effects; Autophagy - physiology; Echinococcosis - drug therapy; Echinococcosis - metabolism; Echinococcosis - parasitology; Echinococcus granulosus - drug effects; Echinococcus granulosus - metabolism; Energy Metabolism - drug effects; Energy Metabolism - physiology; iNOS; Mice; Nitric Oxide Synthase Type II - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology; Spinal cystic echinococcosis
• ISSN: 0006-2952; 1873-2968; 1873-2968
• DOI: 10.1016/j.bcp.2024.116453

[Display omitted] Spinal echinococcosis is one of the most overlooked zoonotic parasitic diseases worldwide. There is currently no safe and effective treatment to eradicate it, and research based on the physiological-metabolic signature of the disease is lacking. Herein, we repurposed agrimol B as a potent anti-hydatid compound and validated its pharmacological mechanism based on arginine uptake as a target through multi-omics sequencing. This herbal component suppressed energy metabolism and activated ROS aggregation by inducing mitochondrial membrane potential depolarization, which subsequently triggered autophagy-dependent apoptosis leading to parasite death. Moreover, we discovered that arginine deprivation induced metabolic changes led to a shift from ornithine to nitrogen oxide synthesis, thus boosting the iNOS enzyme-regulated dominant metabolic pathway. The excess NO targeted the mitochondrial respiratory chain complex IV to disrupt energy metabolic homeostasis and induced a downstream pathological waterfall effect to kill the hydatid. A novel metabolic regulatory mechanism targeting mitochondrial damage for arginine starvation therapy was discovered. Finally, arginine depletion was found to be superior to the anti-spinal echinococcosis effect of albendazole and accompanied by the potential for disc protection. This study unveils the role of arginine in the physiological metabolism of Echinococcus granulosus and reveals the value of targeting arginine metabolism as a potential therapy. In addition, agrimol B is proposed as a promising therapeutic strategy for spinal echinococcosis to block arginine uptake and break this parasite’s metabolic balance.