MPTP mediated Ox-mtDNA release inducing macrophage pyroptosis and exacerbating MCD-induced MASH via promoting the ITPR3/Ca2+/NLRP3 pathway

作者：Qi Zhang, Li Chen, Junyan Liu, Tao Liu, Rui Wang, Xinyi Wu, Shengwei Li · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07302-8 · 被引用次数：7 · 研究领域：Inflammasome and immune disorders、interferon and immune responses、Autophagy in Disease and Therapy

Metabolic Dysfunction-Associated Steatohepatitis (MASH) is a severe and progressive form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), with approximately 25% of adults worldwide suffering from MASLD, of which 20%-30% progress to MASH, and the global incidence continues to rise. Oxidized mitochondrial DNA (Ox-mtDNA) release is a key contributor to MASH. However, its underlying mechanism remains unclear. Clarifying this process may provide a theoretical foundation for MASH treatment. In this study, we separately established MASH models using methionine- and choline deficient diet (MCD) fed mice in vivo and free fatty acid (FFA)-stimulated THP-1 derived macrophages in vitro. Cyclosporin A (CsA: mitochondrial permeability transition pore, mPTP, channel inhibitor) was used to inhibit the release of Ox-mtDNA. 8-OH-dG detection and fluorescent probe were used to evaluate Ox-mtDNA release. Liver lipid deposition was analyzed by Triglyceride (TG) and Oil Red O, and tissue damage were analyzed by aspartate transaminase and alanine aminotransferase (ALT, AST) and H&E staining. Pyroptosis markers, such as cleaved-Caspase1, GSDMD-N, and inflammatory cytokines, such as interleukin − 1β, interleukin 18 (IL-1β, IL-18), were detected by WB, ELISA and transmission electron microscopy (TEM) experiments, and the key pyroptosis pathways activated by Ox-mtDNA were screened by RNA-seq. Finally, ITPR3 was silenced by siRNA in vitro and by Adeno-associated virus (AAV) in vivo r...