Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.
Di(2-ethylhexyl) phthalate (DEHP) is a commonly used plasticizer in polyvinyl chloride (PVC) products. The translocase of the outer mitochondrial membrane 70 (TOM70) mediates the import of various proteins into the mitochondria. This study aims to investigate the influence of DEHP on the nervous system and elucidate the potential protective role of TOM70 in microglia. Mice were administered DEHP at doses of 0, 50, 200, or 500 mg/kg for 28 days. DEHP reduced cortical cell counts, lowered cell density, and caused cell swelling, nuclear pyknosis, and mitochondrial damage in brain cells, with effects exacerbated in the D200 group and most severe in the D500 group. Further investigation revealed that DEHP inhibited TOM70 expression and suppressed the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. These findings suggest that TOM70 may be a potential target against DEHP-induced microglial neuroinflammation via mitochondrial damage. This study provides new insights into therapeutic strategies for tackling neurodegenerative diseases.
危险品化学品经营许可证（带存储）