The study identified a significant association between low TBX15 expression and sorafenib resistance in HCC and established the TBX15-cGAS/STING axis as a key regulator in HCC pathobiology.
Abstract
The drug resistance to targeted therapy in patients with advanced hepatocellular carcinoma (HCC) is gradually increasing. Thus, it is very important to further examine the molecular signaling pathways related to HCC and the corresponding targeted therapy. The study identified a significant association between low TBX15 expression and sorafenib resistance in HCC. TBX15 increased sorafenib sensitivity in HCC cells by inducing ferroptosis in vivo and vitro experiments. Mechanistically, TBX15 promoted the secretion of mitochondrial DNA (mtDNA) into the cytoplasm through the opening of the mitochondrial permeability transition pore, then stimulated the cGAS/STING pathway due to the increased cytosolic mtDNA. TBX15 binds to the HERC5 promoter region, increasing cGAS ISGylation and enhancing its stability. Furthermore, the activation of cGAS/STING pathway increased ferroptosis in HCC cells. Our research underscores TBX15's potential to counteract sorafenib resistance and establishes the TBX15-cGAS/STING axis as a key regulator in HCC pathobiology.
Sorafenib refractoriness severely compromises therapeutic efficacy in hepatocellular carcinoma (HCC). This study identifies ferritin heavy chain 1 pseudogene 7 (FTH1P7) as a critical driver and propagator of sorafenib resistance. FTH1P7 was significantly upregulated in HCC cells resistant to sorafenib. Mechanistically, the self-sustaining FTH1P7/microRNA-182-5p/FOXC1 positive feedback loop maintained high FTH1P7 expression levels in resistant cells. Elevated FTH1P7 functioned as a competing endogenous RNA to the mRNA of its parental gene, ferritin heavy chain 1 (FTH1). Increased FTH1 levels enhanced Fe2+ oxidation, thereby inhibiting ferroptosis-a key anticancer mechanism of sorafenib-thereby conferring resistance. Furthermore, exosomes derived from resistant cells transferred FTH1P7 to sorafenib-sensitive cells, thereby horizontally propagating resistance. To counter sorafenib resistance, we developed a nanoliposome co-delivering sorafenib and FTH1P7-targeting siRNA (SR-siFTH1P7-LIP). This nanomedicine synergistically and effectively silenced FTH1P7 expression and reversed resistance. These results elucidate novel mechanisms of sorafenib resistance, involving FTH1P7-mediated induction and exosomal propagation of ferroptotic resistance, and propose a promising nanomedicine-based strategy to combat sorafenib refractoriness in HCC.
Sisi Cao, C. Xiong, Jiayuan Wu et al.· European Journal of Pharmaco...· 0 citations
Glioblastoma (GBM) is one of the most aggressive and treatment-resistant tumors of the central nervous system, demanding innovative therapeutic strategies. Ferroptosis, an iron-driven lipid peroxidation-dependent cell death, has emerged as a potential means to overcome resistance, with glutathione peroxidase 4 (GPX4) as its key suppressor. MLN4924 (pevonedistat), a first-in-class inhibitor of neddylation currently in clinical trials, has shown strong antitumor activity across multiple malignancies. However, its role in ferroptosis regulation and the underlying molecular mechanisms remain poorly defined. Here, we show that MLN4924 induces ferroptosis, with GPX4 emerging as a central regulatory node. GPX4 expression is elevated in gliomas compared to normal brains, and its higher levels correlate with increased grades and worse patient prognosis. MLN4924 downregulates GPX4 mRNA by suppressing STAT3 signaling, whereas RSL3 directly inhibits GPX4 enzymatic activity. The combination of MLN4924 and RSL3 synergistically potentiates ferroptosis and, in vivo, suppresses subcutaneous tumor growth with a considerable biosafety. Collectively, these findings identify GPX4 as the principal mediator of MLN4924-induced ferroptosis and establish that dual targeting of GPX4 transcription and activity represents a promising therapeutic strategy for GBM.
Zhou Jing, Fangyuan Wang, Hao Li et al.· Carcinogenesis· 0 citations
A novel metabolic-epigenetic mechanism whereby lactate modulates hepatocellular carcinoma sensitivity to targeted therapies through histone lactylation is delineated and suggests AARS1-H4K12la-RAPGEF3 axis may serve as an interventional target to overcome targeted drug resistance, offering a promising strategy to enhance clinical outcomes in HCC patients.
Tanlun Zeng, Wanwan Zhu, Guanqun Sun et al.· Cell Death and Disease· 1 citation
LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62–Keap1–Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.
Yuxin Zhang, Weiqi Xu, Fangling Cheng et al.· Cancer Drug Resistance· 0 citations
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality, and resistance to radiotherapy is a major clinical obstacle. Stress granules (SGs) are involved in tumor adaptation and therapy resistance, but the core regulatory network in LUAD is poorly defined. Here, we identified a 24-gene SG-related prognostic signature through LASSO analysis and singled out YBX1 as a core hub gene due to its high expression in LUAD and strong association with poor patient prognosis. Functional studies showed that YBX1 knockout (YBX1-KO) markedly sensitized LUAD cells to ionizing radiation (IR), as evidenced by reactive oxygen species (ROS) burst, glutathione (GSH) depletion, iron accumulation, and increased lipid peroxidation, all of which were reversed by the ferroptosis inhibitor Ferrostatin-1. Mechanistically, YBX1 directly bound to GPX4 mRNA through its cold shock domain (CSD) and enhanced GPX4 mRNA stability, thereby upregulating GPX4 expression and suppressing ferroptosis. Radiation stress promoted the interaction between YBX1 and the SG nucleating protein G3BP1 via YBX1 amino acids 240-253. Moreover, YBX1 underwent liquid-liquid phase separation (LLPS) through its C-terminal intrinsically disordered region (IDR), and YBX1 condensates co-localized with GPX4 mRNA. Disruption of the YBX1-G3BP1 interaction (Δ240-253) or deletion of the IDR abrogated the ability of YBX1 to stabilize GPX4 mRNA, suppress ferroptosis, and confer radioresistance. In orthotopic LUAD mouse models, YBX1 knockdown synergized with Erastin or IR to inhibit tumor growth, accompanied by enhanced ferroptosis. Together, these findings establish YBX1 as a central hub in the SG network that promotes radioresistance by forming phase-separated condensates that stabilize GPX4 mRNA and block ferroptosis. Targeting YBX1 or its phase separation represents a promising strategy to overcome radiotherapy resistance in LUAD.
