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Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies

Ferroptosis: a promising therapeutic strategy in glioblastoma👇

✅Glioblastoma multiforme (GBM) is an aggressive brain tumor characterized by rapid growth and resistance to conventional therapies. Recent research highlights ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, as a novel and promising approach for GBM treatment.

✅One key mechanism underlying ferroptosis in GBM is glutathione depletion. Inhibition of the cystine/glutamate antiporter system (xCT) limits cystine uptake, leading to reduced glutathione synthesis. As a consequence, the antioxidant enzyme GPX4 becomes inactivated, impairing the cell’s ability to detoxify lipid peroxides.

✅Lipid peroxidation is a central event in ferroptosis. Polyunsaturated fatty acids (PUFAs) incorporated into membrane phospholipids are highly susceptible to oxidative damage. Their conversion into peroxidized phospholipids (PL-PUFA-PE) disrupts membrane integrity and drives lethal oxidative stress.

✅Iron metabolism further amplifies ferroptotic signaling in GBM cells. Elevated intracellular iron, particularly the FeÂČâș pool, catalyzes redox reactions that generate reactive oxygen species (ROS). This iron-driven ROS production accelerates lipid peroxidation and pushes tumor cells toward ferroptotic death.

✅Collectively, glutathione depletion, GPX4 inactivation, uncontrolled lipid peroxidation, and dysregulated iron metabolism converge to induce ferroptosis. Targeting these interconnected pathways offers a potential strategy to overcome therapy resistance and selectively eliminate GBM cells.

Continue reading “Ferroptosis as a therapeutic target in glioblastoma: Mechanisms and emerging strategies” | >

A glycolytic shunt via the pentose phosphate pathway is a metabolic checkpoint for nervous system sensory homeostasis and axonal regeneration

Pentose phosphate pathway in axonal regeneration.

Various signaling pathways play an important role in neuronal homeostasis and regeneration.

The researchers in this study determine that the pentose phosphate pathway (PPP) plays a dual role in enabling homeostatic and regenerative adaptations to environmental stimuli and injuries.

They show that sciatic nerve axoplasms are enriched PPP and maintains redox balance via NADPH production but following sciatic nerve injury, the PPP is required for regeneration by fueling ribonucleotide synthesis through ribose-5-phosphate.

However, after spinal cord injury (SCI), PPP remain inactive and neuronal transketolase overexpression or oral ribose supplementation, promotes metabolic reprogramming, restores sensory and motor axonal growth. sciencenewshighlights ScienceMission https://sciencemission.com/pentose-phosphate-pathway-is-a-metabolic-checkpoint

The pentose phosphate pathway plays a dual role in enabling homeostatic and regenerative adaptations to environmental stimuli and injuries and can be leveraged to promote regeneration and recovery after spinal cord injury.

Continue reading “A glycolytic shunt via the pentose phosphate pathway is a metabolic checkpoint for nervous system sensory homeostasis and axonal regeneration” | >

The contribution of the membrane-bound complement regulatory proteins CD46 and CD55 in phases of acute lymphocytic leukemia and acute myelogenous leukemia

As for decay accelerating factor (DAF); also known as CD55, it is a type I cell surface protein that forms a single chain anchored to the membrane by glycosylphosphatidylinositol (GPI). It binds C3b and C4b inhibiting thereby the formation of C3 convertase and decreasing its half-life, thus providing a protective barrier threshold for plasma membranes of normal autologous cells against complement deposition and activation9,10.

The role of the complement system in cancer is complicated and has been debated for long. Malignant transformation is generally accompanied by genetic and epigenetic modifications which drastically alter patterns of glycosylation, cell-surface proteins and phospholipids11. These alterations can be identified by innate and adaptive immune mechanisms that guard the host against cancer development12. This is the known basis of the immune surveillance hypothesis. There is no direct evidence to support the argument that complement is able to eradicate emerging tumors. Nevertheless, taking into consideration that complement is intended for the recognition of non-self-elements, it is assumed that alterations in the tumor cell membranes’ composition render these cells as targets for complement recognition13. However, the relationship between inflammation and cancer is complicated and subject to contradictory forces14. Therefore, while acute responses are considered a vital part of the defense against cancerous cells, continuous inflammation in the tumor microenvironment increases the threat of neoplastic transformation and has several tumor-promoting effects15.

The current study aims at investigating the expression levels of mCRPs; CD46 and CD55 in the acute lymphocytic leukemia and acute myelogenous leukemia and to further elucidate its role in Egyptian cancer patients. To the best of our knowledge this study is one of very few studies tackling the complicated role of the complement system in acute leukemia.

Apple’s Historic Quarter Doesn’t Change the Need for AI Reckoning

Apple’s blockbuster holiday quarter was impressive — but it shouldn’t give cover to avoid an AI reckoning. Also: A new MacBook Pro is planned for the macOS 26.3 release cycle; the company explores a clamshell follow-up to its upcoming foldable phone; and an updated AirTag finally rolls out.

Last week in Power On: Inside Apple’s AI shake-up and its plans for two new versions of Siri powered by Gemini.

The LLM Revolution Is Over. The Physical AI Revolution Is Coming Fast

On stage at Imagination In Action’s AI Summit in Davos with John Werner, founder and CEO of Imagination In Action, Yann LeCun discusses the inevitable shift from current large language models to a new paradigm of “physical AI” based on world models. LeCun opens up about the importance of maintaining open-source research to mitigate the geopolitical risks of concentrated AI power.

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Speaking multiple languages appears to keep the brain younger for longer

A study of 86,000 adults across Europe links multilingualism to slower biological aging. Researchers found that people who speak multiple languages tend to maintain better cognitive function and physical health than their monolingual peers.

Zanidatamab in HER2-Positive Metastatic Biliary Tract Cancer: Final Results From HERIZON-BTC-01

Among adults with treatment-refractory, HER2-positive BiliaryTractCancer, zanidatamab produced sustained, meaningful clinical responses and extended survival compared to prior standards.

In patients with immunohistochemistry (IHC) 3+ tumors, response rates and overall survival were notably higher than those with IHC 2+ tumors, substantiating the use of reflex IHC testing to identify candidates for HER2-targeted therapy.

Safety remained consistent over 33 months of follow-up, and the ongoing HERIZON-BTC-302 phase 3 trial is assessing zanidatamab alongside first-line standard care in this setting.

This follow-up analysis of the phase 2 HERIZON-BTC-01 trial evaluates the efficacy, patient-reported outcomes, and safety profile of zanidatamab in patients with ERBB2-amplified biliary tract cancer with a HER2 immunohistochemistry score of 3+ or 2+ after 33 months of follow-up.

EGFR activation sensitizes trigeminal NMDA receptors to promote pain and morphine analgesic tolerance in oral cancer

Oral squamous cell carcinoma (OSCC) is a painful disease that severely impairs eating, drinking, and talking (1–5). Patients with OSCC are less opioid responsive and develop opioid tolerance quicker than patients with other chronic pain conditions (6, 7). Escalating doses of opioids are required as tolerance develops, causing not only severe adverse effects (6) such as addiction but also prolonged hospitalizations and increased readmission rate in patients (8). The mechanisms underlying oral cancer pain and opioid tolerance are not well understood.

Epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinases (RTKs) subfamily named HER/ERBB that is aberrantly expressed in 80 to 100% of the OSCC cases (9–11). EGFR antagonism including antibodies and tyrosine kinase inhibitors (TKIs) are US Food and Drug Administration (FDA) approved to treat many cancers, including OSCC (12–14). Clinical studies report pain relief in patients with neuropathic pain, including those associated with cancer after treatment with EGFR inhibitors (15, 16). Human genetic studies find associations between painful disease conditions and EGFR and its ligands, such as epiregulin, heparin-binding EGF (HB-EGF), and transforming growth factor–α (TGFα) (17–19). In animal models, HB-EGF directly causes dorsal root ganglion (DRG) cell excitation and elicits pain-like behaviors, whereas epiregulin mainly works in conjunction with underlying inflammation or tissue injury to generate pain (17, 19, 20). EGFR has also been implicated in opioid tolerance in human (21) and animal studies (20, 22, 23). Although elegant mechanistic studies suggest that EGFR can activate various pathways—through the ion channel transient receptor potential vanilloid 1 (TRPV1), the kinase cascade phosphatidylinositol 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR), the protease matrix metalloproteinase–9 (MMP-9), or the oncogene KRAS [to tetrahydrobiopterin (BH4)]—to increase pain sensitivities in mice (17, 24), these studies were done at the spinal level of noncancer pain models. It has been shown that EGFR involvement in pain is ligand and disease dependent (17, 25, 26), which warrants the investigation of EGFR signaling both in the setting of oral cancer pain that involves the trigeminal system and in opioid analgesic tolerance.

In this study, we aimed to determine how EGFR signaling contributes to oral cancer pain and opioid tolerance. We found that EGFR activation sensitizes trigeminal ganglion (TG) neurons and enhances glutamate N-methyl-d-aspartate receptor (NMDAR) signaling, resulting in heightened cancer pain and diminished opioid analgesic efficacy. EGFR ligands abundant in the OSCC tumor microenvironment trigger calcium influx, NMDAR phosphorylation, and protein kinase C (PKC) up-regulation in TG neurons. Last, we showed that EGFR activation induces presynaptic and postsynaptic hypersensitivity of NMDARs in the trigeminal nucleus caudalis (TNc) of the brainstem. Together, these findings establish EGFR-mediated NMDAR sensitization as a central mechanism underlying oral cancer pain and opioid tolerance and highlight EGFR as a promising therapeutic target.

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