A recent study at Nanjing University of Chinese Medicine, published in Genes & Diseases , reported that neoliensisnine (NeoL)—a tribenzylisoquinoline alkaloid isolated from Plumula nelumbinis (the embryo of Nelumbo nucifera Gaertn.)—exerts potent anti-T-CM activity and elucidated its mechanism of action.
Preliminary findings revealed that NeoL has a strong cytotoxic effect on T-CM cells. Previous studies have shown that the stimulator of interferon genes (STING) pathway is essential in T lymphocytes and plays a critical role in antitumor immunity. In this study, the authors observed high STING expression in T-CM cells, which was reduced upon treatment with NeoL. Molecular docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) analyses showed that NeoL binds directly to STING with high affinity and thereby exerts a stronger inhibitory effect, suggesting that NeoL induces T-CM cell death by promoting STING degradation.
Research over the years has shown that STING is degraded via the lysosomal pathway through ESCRT-driven microautophagy. In the current study, the authors demonstrated that NeoL, by regulating TUBA1B—an important microtubule isoform involved in cytoskeleton formation—promotes STING degradation via the microtubule–lysosome pathway. Furthermore, TUBA1B mediates NeoL-induced lysosomal trafficking of STING by disrupting lysosomal cholesterol homeostasis.
Additionally, treatment with NeoL induces lysophagy and lysosomal membrane permeabilization, which lead to lysosomal damage and lysosome-dependent cell death in T-CM. The authors also showed that STING, microtubules, and cholesterol accumulation play critical roles in mediating NeoL-induced lysosomal dysfunction. The inhibitory effect of NeoL on T-CM was also validated in vivo .
In conclusion, this study shows that NeoL is a safe and efficient candidate drug that, by promoting lysosome-dependent cell death via the TUBA1B/STING/cholesterol axis, inhibits T-CM—thus positioning it as a promising therapeutic agent to improve treatment outcomes for T-CMs.
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