Hypoxia is commonly observed in solid tumors and contributes to the resistance of DNA damage drugs. However, the mechanisms behind this resistance are still unclear. In this study, we aimed to explore the effects of hypoxia-induced exosomes on non-small cell lung cancer (NSCLC).

The active ingredient of the traditional Chinese medicine comfrey is shikonin, a naphthoquinone compound. The focus of this study was to investigate the effect of shikonin on the proliferation, invasion, migration, and chemoresistance of non-small cell lung cancer (NSCLC) cells, and to explore its underlying molecular biological mechanisms. The results show that shikonin inhibited the viability, proliferation, invasion, and migration of NSCLC cells A549 and PC9, and induced apoptosis. As the inhibitor of pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, shikonin inhibited glucose uptake and the production of lactate, the final metabolite of aerobic glycolysis. In vivo chemotherapeutic assay showed that shikonin reduced the tumor volume and weight in NSCLC mice model and increased the sensitivity to cisplatin chemotherapy. Histoimmunology experiments showed the combination of shikonin and cisplatin downregulated the expression of PKM2 and its transcriptionally regulated downstream gene glucose transporter 1 (Glut1) in tumor tissue. In an assessment of glucose metabolism, micro-PET/CT data showed a combination of shikonin and cisplatin inhibited the fluorodeoxy glucose (¹⁸F-FDG) uptake into tumor. Since exosomal PKM2 affected the sensitivity to cisplatin in NSCLC cells, we also demonstrated shikonin could inhibit exosome secretion and exosomal PKM2 through the administration of exosomal inhibitor GW4869. Furthermore, shikonin sensitized cisplatin treatment by reducing the extracellular secretion of exosomal PKM2. In conclusion, we suggest that shikonin not only inhibits PKM2 intracellularly but also reduces glycolytic flux and increases cisplatin sensitivity through the exosomal pathway. GRAPHICAL ABSTRACT

Chemoresistance challenges the clinical treatment of colorectal cancer and requires an urgent solution. Isocitrate dehydrogenase 1 (IDH1) is a key enzyme involved in glucose metabolism that mediates the malignant transformation of tumors. However, the mechanisms by which IDH1 is involved in colorectal cancer cell proliferation and drug resistance induction remain unclear. In this study, we found that IDH1 was highly expressed in human colorectal cancer tissues and could be used to indicate a high-grade tumor. In vitro gene overexpression and knockdown were used to determine whether IDH1 promoted the proliferation of the colorectal cancer cell line HCT8 and resistance to 5-Fluorouracil (5FU). Further studies have shown that the 5FU-resistant cell line, HCT8FU, secreted exosomes that contained a high level of IDH1 protein. The exosomal IDH1 derived from 5FU-resistant cells enhanced the resistance of 5FU-sensitive cells. Metabolic assays revealed that exosomes derived from 5FU-resistant cells promoted a decrease in the level of IDH1-mediated NADPH, which is associated with the development of 5FU resistance in colorectal cancer cells. Therefore, exosomal IDH1 may be the transmitter and driver of chemoresistance in colorectal cancer and a potential chemotherapy target.

Rationale: Non-small cell lung cancer (NSCLC) is a predominant cause of cancer-related mortality, with its progression and treatment resistance significantly influenced by cancer stem cells (CSCs) and their complex intercellular communication mechanisms. Small extracellular vesicles (sEVs) have emerged as pivotal mediators of intercellular signaling, affecting tumor microenvironment modulation and therapeutic resistance. This study investigates the role of CSC-derived sEVs in transmitting stemness traits through the selective sorting of pyruvate kinase M2 phosphorylated at the Y105 site (pY105-PKM2), mediated by the adaptor protein IQGAP1, which supports CSC maintenance and drug resistance in NSCLC.

Lenvatinib resistance remains a major challenge in hepatocellular carcinoma (HCC) treatment, highlighting the need for novel therapeutic strategies. Cuproptosis, a copper-dependent form of cell death, has been increasingly implicated in cancer progression. Quercetin, a naturally occurring bioactive flavonol known to modulate mitochondrial metabolism and multiple oncogenic signaling pathways, has emerged as a potential sensitizer. This study aimed to elucidate the molecular mechanisms by which lenvatinib-resistant HCC cells evade copper-induced cell death and to evaluate whether quercetin enhances ES-Cu-induced cuproptosis by targeting FDX1 and reprogramming mitochondrial metabolism. Integrated methodologies including bioinformatics analysis, clinical specimen profiling, qRT-PCR, cell proliferation assays, intracellular copper quantification, and Western blot were employed to investigate (1) the insensitivityof lenvatinib-resistant hepatocellular carcinoma (HCC) to cuproptosis but target FDX1 can reverse it(2) the potential of quercetin-ES-Cu combinatorial treatment to reverse drug resistance. Furthermore, subcutaneous xenograft models, mitochondrial OCR measurements, mitochondrial enzyme activity/functional assays, and bio-quercetin administration analyses (immunofluorescence, co-immunoprecipitation) were systematically implemented in both in vitro and in vivo settings to delineate the FDX1-mediated cuproptosis activation mechanism and validate therapeutic efficacy. Lenvatinib-resistant HCC cells displayed downregulation of cuproptosis-related genes (FDX1, DLAT) and impaired copper accumulation. Quercetin bind with FDX1, enhanced mitochondrial OCR, and synergistically increased intracellular copper accumulation with ES-Cu, leading to lipoylated protein aggregation, mitochondrial dysfunction, and copper-induced cell death. In vivo, quercetin plus ES-Cu significantly suppressed tumor growth without evident toxicity. This study elucidates the mechanisms by which lenvatinib-resistant HCC cells evade cuproptosis, highlighting the therapeutic potential of quercetin and ES-Cu combination treatment as a novel strategy to overcome lenvatinib resistance in HCC.

Long non-coding RNA AC020978 (lncRNA AC020978) served as an oncogenic regulator of non-small cell lung cancer (NSCLC). However, the function of AC020978 in regulating NSCLC metastasis and the potential molecular mechanism remains largely unknown. In this study, we evaluated the expression levels of AC020978 in a series of NSCLC tissues using fluorescence in situ hybridization (FISH) assays, and found that higher AC020978 expression levels were closely associated with metastasis and unfavorable prognosis. Functional studies showed that AC020978 promoted NSCLC migration and invasion both in vitro and in vivo. Further investigation demonstrated that AC020978 interacted with malate dehydrogenase 2 (MDH2) and maintained MDH2 stability. Knockdown of MDH2 weakened the facilitating effect on cell metastasis and 2-hydroxyglutarate (2-HG) metabolism in AC020978-overexpressed NSCLC cells. RNA sequencing, bioinformatic analysis, and western blotting revealed that AC020978 was associated with AKT signaling pathway. Taken together, our findings revealed that AC020978 might serve as a prognostic biomarker and activate AKT pathway by stabilizing MDH2, leading to metastasis and progression of NSCLC.