Jian Xiao,Nana Feng,Qiushi Li,Xianghui Cao,Qingqing Huang,Biyu Zhou,Zhenrui Fan,Liping Wei,Yang Liu
Ferroptosis is gaining attention as a potential cancer immunotherapy strategy, as it can stimulate antitumor responses by enhancing dendritic cell (DC) activation and the infiltration of cytotoxic T cells (CTLs). However, cancer cells often develop resistance to ferroptosis, reducing the effectiveness of existing treatments. This study demonstrates a novel mitochondria-targeted ferroptosis inducer, designated mitoFePDA@R, which is engineered to achieve a “closed-loop” cancer immunotherapy strategy of ferroptosis induction, antitumor immune activation, and ferroptosis enhancement. In this strategy, mitoFePDA@R is designed to release Fe 2+ and the mitoGPX4 inhibitor RSL3 within tumor mitochondria, thereby effectively inducing ferroptosis and activating strong antitumor immune responses. Additionally, interferon γ ( IFN-γ) released from CTLs inhibits GSH synthesis, which further enhances the ferroptosis sensitivity of tumor cells to form a “closed-loop” strategy. In vitro studies indicated that mitoFePDA@R induced strong ferroptosis in tumor cells by accumulating lipid peroxides (LPO) in mitochondria (which lacks mitochondria targeting). Animal studies confirmed that mitoFePDA@R effectively triggered ferroptosis and activated subsequent antitumor immune responses, leading to significant tumor growth inhibition. This provides a viable and effective strategy for ferroptosis-associated cancer immunotherapy.
Zi-Han Xu,Ming-Min Xie,Chun-Lan Xie,Xian-Wen Yang,Jun-Song Wang
Neuroinflammation and neuronal cell death are leading causes of death in the elderly and underlie various neurodegenerative diseases. These diseases involve complex pathophysiological mechanisms, including inflammatory responses, oxidative stress, and ferroptosis. Compounds derived from deep-sea fungi exhibit low toxicity and potent neuroprotective effects, offering a promising source for drug development. In this study, we isolated 44 natural products from deep-sea-derived fungi and identified isobisvertinol (17) as a compound with anti-inflammatory and ferroptosis-inhibiting effects. Using LPS-induced microglial inflammation and RSL3-induced neuronal ferroptosis models, we found that17targets TLR4 to provide neuroprotection. Molecular docking studies revealed that17inhibits TLR4 activation by occupying the hydrophobic pocket at the TLR4-MD2 binding site. Additionally,17suppresses TLR4, reducing p38 MAPK phosphorylation, and inhibits ferroptosis by decreasing lipid peroxidation and modulating mitochondrial membrane potential. Metabolomic analysis showed that17rescues alterations in multiple metabolic pathways induced by RSL3 and increases levels of antioxidant metabolites, including glutamine, glutamate, and glutathione. In summary, our results indicate that isobisvertinol (17) targets TLR4 in neural cells to reduce inflammation and inhibit p38 MAPK phosphorylation, while regulating metabolic pathways, mainly GSH synthesis, to provide antioxidant effects and prevent ferroptosis in neurons.
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