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Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters, in which oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacologic inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the antiestrogen drug fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer. Significance: Persister cancer cells that survive endocrine therapy exhibit increased energetic dependence upon mitochondria for survival and tumor regrowth potential, indicating that therapies targeting this metabolic dependency could help prevent disease recurrence. Show less

Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropathy (PN) that affects ∼70% of patients. PN is caused by selective accumulation of the platinum drugs in the dorsal root ganglia (DRG), which overexpress transporters for cisplatin and oxaliplatin. To date, no drug is recommended for the prevention of PN. We report that Pt(IV) prodrugs of cisplatin or oxaliplatin do not induce neuropathic pain in mice, likely due to the lower accumulation of platinum in the DRG compared with Pt(II) drugs. Moreover, the multitargeting prodrug that combines cisplatin with paclitaxel, both strong inducers of PN, efficiently inhibited tumor growth in vivo without inducing neuropathic pain. The high antitumor efficacy of Pt(IV) prodrugs and their micellar counterparts and the low level of neuropathic pain associated with them make them ideal candidates for clinical use in cancer therapy. Show less

Introduction Mitochondria are essential organelles for many aspects of cellular homeostasis. They play an indispensable role in the development and progression of diseases, particularly cancer which is a major cause of death worldwide. We analyzed the scientific research output on mitochondria and cancer via PubMed and Web of Science over the period 1990–2023. Methods Bibliometric analysis was performed by extracting data linking mitochondria to cancer pathogenesis over the period 1990–2023 from the PubMed database which has a precise and specific search engine. Only articles and reviews were considered. Since PubMed does not support analyses by countries or institutions, we utilized InCites, an analytical tool developed and marketed by Clarivate Analytics. We also used the VOSviewer software developed by the Centre for Science and Technology Studies (Bibliometric Department of Leiden University, Leiden, Netherlands), which enables us to graphically represent links between countries, authors or keywords in cluster form. Finally, we used iCite, a tool developed by the NIH (USA) to access a dashboard of bibliometrics for papers associated with a portfolio. This module can therefore be used to measure whether the research carried out is still basic, translational or clinical. Results In total, 169,555 publications were identified in PubMed relating to ‘mitochondria’, of which 34,949 (20.61%) concerned ‘mitochondria’ and ‘dysfunction’ and 22,406 (13.21%) regarded ‘mitochondria’ and ‘cancer’. Hence, not all mitochondrial dysfunctions may lead to cancer or enhance its progression. Qualitatively, the disciplines of journals were classified into 166 categories among which cancer specialty accounts for only 4.7% of publications. Quantitatively, our analysis showed that cancer/neoplasms in the liver (2569 articles) were placed in the first position. USA occupied the first position among countries contributing the highest number of publications (5695 articles), whereas Egypt came in the thirty-eight position with 84 publications (0.46%). Importantly, USA is the first-ranked country having both the top 1% and 10% impact indicators with 207 and 1459 articles, respectively. By crossing the query ‘liver neoplasms’ (155,678) with the query ‘mitochondria’ (169,555), we identified 1336 articles in PubMed over the study period. Among these publications, research areas were classified into 65 categories with the highest percentage of documents included in biochemistry and molecular biology (28.92%), followed by oncology (23.31%). Conclusions This study underscores the crucial yet underrepresented role of mitochondria in cancer research. Despite their significance in cancer pathogenesis, the proportion of related publications remains relatively low. Our findings Supplementary Information The online version contains supplementary material available at https://​doi.​org/​10.​1007/​s12672-​025-​ 02139-5. * Abeer El Wakil, abeer_elwakil@alexu.edu.eg; Patrick Devos, patrick.devos@univ-lille.fr; Heba Abdelmegeed, hn.abdelmegeed@ nrc.sci.eg; Alaa Kamel, alaa.kamel_pg@alexu.edu.eg | 1Department of Biological and Geological Sciences, Faculty of Education, Alexandria University, Alexandria 21526, Egypt. 2Université Lille, Lillometrics, 59000 Lille, France. 3CHU Lille, Direction de la Recherche et de l’Innovation, 59000 Lille, France. 4Department of Chemistry of Natural Compounds, National Research Centre, Giza, Egypt. 5Department of Zoology, Faulty of Science, Alexandria University, Alexandria, Egypt. Discover Oncology (2025) 16:517 | https://doi.org/10.1007/s12672-025-02139-5 Vol.:(0123456789) Research Discover Oncology (2025) 16:517 | https://doi.org/10.1007/s12672-025-02139-5 highlight the need for further research to deepen our understanding of mitochondrial mechanisms in cancer, which could pave the way for new therapeutic strategies. Graphical Abstract Show less

The convergence of artificial intelligence (AI) and genomics is redefining cancer drug discovery by facilitating the development of personalized and effective therapies. This review examines the transformative role of AI technologies, including deep learning and advanced data analytics, in accelerating key stages of the drug discovery process: target identification, drug design, clinical trial optimization, and drug response prediction. Cutting-edge tools such as DrugnomeAI and PandaOmics have made substantial contributions to therapeutic target identification, while AI's predictive capabilities are driving personalized treatment strategies. Additionally, advancements like AlphaFold highlight AI's capacity to address intricate challenges in drug development. However, the field faces significant challenges, including the management of large-scale genomic datasets and ethical concerns surrounding AI deployment in healthcare. This review underscores the promise of data-centric AI approaches and emphasizes the necessity of continued innovation and interdisciplinary collaboration. Together, AI and genomics are charting a path toward more precise, efficient, and transformative cancer therapeutics. Show less

Hyperthymesia has been described in individuals, who show superior retrieval capacities in autobiographical memory. This condition differs from superior memory, which refers to the supranormal ability to acquire and recall new information but not autobiographical information. The process responsible for hyperthymesia is still largely unknown and most knowledge come from case studies, showing individual with impressive superior capacities to retrieve autobiographical memories. Here, we describe a case of hyperthymesia with an objective as well as a subjective assessment of mental time travel abilities in different temporal distances. This is the first observation of hyperthymesia with a full evaluation of mental time travel capacities in different temporal distances, encompassing the individual capacity to retrieve personal events from the personal past as well as to foresee personal events in the future. This observation could pave the way to further research on superior autobiographical abilities, studied in the context of personal temporality. Show less

Transcription-coupled repair (TCR) and R-loops are two interrelated processes critical to the maintenance of genome stability during transcription. TCR, a specialized sub-pathway of nucleotide excision repair, rapidly removes transcription-blocking lesions from the transcribed strand of active genes, thereby safeguarding transcription fidelity and cellular homeostasis. In contrast, R-loops, RNA-DNA hybrid structures formed co-transcriptionally, play not only regulatory roles in gene expression and replication but can also contribute to genome instability when persistently accumulated. Recent experimental evidence has revealed dynamic crosstalk between TCR and R-loop resolution pathways. This review highlights current molecular and cellular insights into TCR and R-loop biology, discusses the impact of their crosstalk, and explores emerging therapeutic strategies aimed at optimizing DNA repair and reducing disease risk in conditions such as cancer and neurodegenerative disorders. Show less

This study presents the chemical synthesis and biological evaluation of a series of gold(I)-N-heterocyclic carbene complexes as potential anticancer agents. The compounds demonstrated broad activity against various cancer cell lines, exhibiting cytotoxicity in the low micromolar range. Mechanistic investigations revealed that these complexes preferentially accumulate in the mitochondria of cancer cells, where they induce the generation of reactive oxygen species and lipid peroxides, ultimately triggering ferroptosis. Further studies in multicellular tumor spheroids confirmed the compounds' ability to penetrate three-dimensional cellular structures and effectively eradicate them at low micromolar concentrations. This work represents the first known example of a gold(I)-N-heterocyclic carbene complex inducing ferroptosis, expanding the therapeutic potential of gold(I)-based metallodrugs. Show less

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity have hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared with healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243, and IACS-010759 and the potential of mitochondria-targeted OXPHOSi and their influence on reactive oxygen species production. Furthermore, the effect of the mitochondria-targeting moiety triphenylphosphonium on mitochondria is discussed as it affects mitochondrial bioenergetics. Show less

Abstract Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less

High-Grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, known for its high aggressiveness and extensive genomic alterations. Typically diagnosed at an advanced stage, HGSOC presents formidable challenges in drug therapy. The limited efficacy of standard treatments, development of chemoresistance, scarcity of targeted therapies, and significant tumor heterogeneity render this disease incurable with current treatment options, highlighting the urgent need for novel therapeutic approaches to improve patient outcomes. In this study we report a straightforward and stereoselective synthetic route to novel Pd(II)-vinyl and -butadienyl complexes bearing a wide range of monodentate and bidentate ligands. Most of the synthesized complexes exhibited good to excellent in vitro anticancer activity against ovarian cancer cells. Particularly promising is the water-soluble complex bearing two PTA (1,3,5-triaza-7-phosphaadamantane) ligands and the Pd(II)-butadienyl fragment. This compound combines excellent cytotoxicity towards cancer cells with substantial inactivity towards non-cancerous ones. This derivative was selected for further studies on ex vivo tumor organoids and in vivo mouse models, which demonstrate its remarkable efficacy with surprisingly low collateral toxicity even at high dosages. Moreover, this class of compounds appears to operate through a ferroptotic mechanism, thus representing the first such example for an organopalladium compound. Show less

Hepatic ischemia-reperfusion injury (HIRI) is one of the main causes of liver insufficiency and failure after liver surgery. However, the effectiveness of current methods of treating HIRI is generally limited. Previous studies have shown that hydrogen sulfide (H₂S) has a beneficial effect on HIRI, and an appropriate concentration of H₂S can significantly reduce HIRI by protecting the mitochondria. Therefore, establishing an accurate imaging platform for monitoring variations in mitochondrial H₂S is an effective strategy for anti-HIRI drug discovery and efficacy evaluation. To this end, a cyclometalated iridium(III) complex-based probe, Cym-Ir-EDB, was developed for detecting mitochondrial H₂S in HIRI. Cym-Ir-EDB possesses good sensitivity, high selectivity, negligible cytotoxicity, and excellent mitochondrial-targeting ability, rendering it a promising imaging tool for analyzing variations in mitochondrial H₂S in HIRI cells. Using Cym-Ir-EDB as a probe, anti-HIRI drugs were screened from isothiocyanates by monitoring variations in mitochondrial H₂S in HIRI cells, for the first time. Moreover, the dynamics of mitochondrial H₂S in HIRI cells were visualized and the response of HIRI to treatment with the screened erucin was monitored. The findings indicate that Cym-Ir-EDB can serve as a useful imaging platform for the precise imaging of mitochondrial H₂S in HIRI, thereby contributing to anti-HIRI drug discovery and efficacy evaluation. Show less

Antimicrobial molecule discovered in soil from lab technician’s garden — plus, a huge study assessing the nuances of humans’ impacts on biodiversity. Hear the biggest stories from the world of science | 26 March 2025 Show less