An Autophagy-Associated MITF–GAS5–miR-23 Loop Attenuates Vascular Oxidative and Inflammatory Damage in Sepsis

Background: Sepsis induces GAS5 expression in the vascular endothelium, but molecular mechanism is unclear, as role of sepsis. Methods and results: We observed that endothelium was significantly upregulated a sepsis mouse model. ChIP-PCR EMSA confirmed oxidative stress (OS)-activated MiT–TFE transcription factor (MITF, TFE3, TFEB)-mediated transcription. In vitro, overexpression attenuated OS inflammation endothelial cells (ECs) while maintaining structural functional integrity mitochondria. vivo, reduced tissue ROS levels, maintained barrier function to reduce leakage, ultimately sepsis-induced lung injury. Luciferase reporter assays revealed protected MITF from degradation by sponging miR-23, thereby forming positive feedback loop consisting MITF, GAS5, miR-23. Despite fact OS-activated MITF–GAS5–miR-23 boosted MITF-mediated p62 transcription, ECs do not need increase mitophagy exert mitochondrial quality control since Nrf2 exists. Compared mitophagy, MITF-transcribed prefers facilitate autophagic Keap1 through direct interaction, relieving inhibition Keap1, indicating can upregulate at both transcriptional posttranscriptional levels. Following this, demonstrated also transcribe revealing there reciprocal regulatory association between Nrf2. Conclusion: sepsis, ROS-activated integrated antioxidant autophagy systems p62, which dynamically regulate level type autophagy, well anti-inflammatory effects.