Vimal Arora

Ferroptosis is an iron-dependent form of regulated cell death driven by lethal lipid peroxidation and has emerged as a promising therapeutic vulnerability in cancer. Increasing evidence highlights its critical role in controlling tumor progression, overcoming therapeutic resistance, and enhancing antitumor immunity. Recent studies have identified the ubiquitin–proteasome system (UPS), particularly deubiquitinases (DUBs), as key regulatory nodes that determine ferroptotic susceptibility and represent attractive therapeutic targets. DUBs promote cancer cell survival and drug resistance by modulating the ubiquitination, stability, and functional activity of central ferroptosis regulators, thereby enabling tumor cells to evade oxidative stress and treatment-induced cytotoxicity. Several DUBs, such as OTUD5, OTUB1, USP7, USP14, USP22, and USP35, have been recognized as potent suppressors of ferroptosis that contribute to resistance against chemotherapy, radiotherapy, and targeted therapies. Importantly, pharmacological inhibitors or genetic silencing of these DUBs can reactivate ferroptotic cell death, resensitize resistant tumors to conventional and targeted therapies, and improve overall therapeutic outcomes. These findings position DUBs as highly actionable drug targets and support the development of DUB-directed inhibitors as ferroptosis-sensitizing agents in cancer treatment. Beyond regulating intrinsic tumor cell survival, DUB-mediated ferroptosis control also influences tumor–immune interactions and the tumor microenvironment, thereby affecting immune evasion and responsiveness to immunotherapy. This review comprehensively summarizes current progress in targeting DUB-mediated ferroptosis regulation, highlights emerging pharmacological strategies against UPS components, and discusses their translational potential for overcoming therapeutic resistance and improving cancer treatment efficacy.

Neurovascular coupling (NVC) maintains appropriate cerebral blood flow (CBF) in response to neuronal activity, and its disturbance, known as neurovascular uncoupling (NVU), is increasingly recognised as a major contributor to neurodegenerative disease. Alzheimer’s disease (AD) NVU is caused by Aβ buildup, tau pathology, endothelial dysfunction, and persistent neuroinflammation, leading to poor CBF control and blood–brain barrier (BBB) disintegration. Parkinson’s disease (PD) is characterised by α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, and dopaminergic neuronal loss, all of which impede cerebrovascular regulation. These disease-specific mechanisms interact via similar vascular pathways, establishing NVU as a critical connection between neuronal degeneration and cerebrovascular dysfunction. This study highlights the critical role of NVU in neurodegeneration by investigating shared and disease-specific processes in AD and PD. Tau pathology disturbs vascular regulation in AD, whereas dopaminergic neuron loss impairs cerebrovascular control in PD. Both Aβ and α-synuclein are linked to endothelial dysfunction and oxidative stress, albeit originating in different pathologies. Comparative analysis reveals distinct vascular abnormalities in each condition, as well as shared processes such as inflammation and BBB disruption. The study also covers developments in biomarker discovery and neuroimaging techniques that allow for exact characterisation of NVU, facilitating early diagnosis and treatments. In addition, lifestyle changes and pharmacological treatments for oxidative stress and endothelial injury are being examined. This study highlights the significance of NVU as a fundamental pathogenic mechanism, underscoring its importance for comprehending disease development and formulating novel therapeutic strategies.

Leukemia, characterized by the uncontrolled proliferation of abnormal white blood cells, encompasses several subtypes, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). It presents a significant challenge in treatment due to its complex biology and the presence of drug resistance. Autophagy, a cellular process responsible for degrading and recycling cellular components, plays a dual role in leukemia. On one hand, autophagy helps cancer cells survive and adapt to stressors, including chemotherapy, promoting drug resistance. On the other hand, it can also function as a tumor suppressor by enhancing sensitivity to treatment. MicroRNAs (miRNAs), small RNA molecules that regulate gene expression, are crucial in modulating autophagy-related genes and signaling pathways in leukemia. Dysregulated miRNAs can either inhibit or enhance autophagy, influencing leukemia progression and response to therapy. Targeting the interaction between autophagy and miRNAs presents a novel therapeutic strategy to overcome drug resistance and improve leukemia treatment outcomes. By understanding the molecular mechanisms of autophagy and miRNAs, new treatment strategies could be developed that focus on restoring proper autophagic function and miRNA regulation, ultimately enhancing the effectiveness of chemotherapy and reducing side effects. This review explores the dual roles of autophagy and miRNAs in leukemia, providing a deeper insight into their interplay and their potential for improving therapeutic approaches. Graphical Abstract

The nervous and immune systems, though traditionally studied as separate entities, are now recognized as deeply interconnected networks that jointly regulate tumor initiation, progression, and therapeutic response. Neural elements extend into the tumor microenvironment where they interact with immune cells, shaping processes such as proliferation, invasion, and metastasis. Through neurotransmitters, neuropeptides, and bidirectional signaling with the brain, nerves influence leukocyte recruitment, functional activity, and immune tone. Stress, circadian disruption, and gut–brain interactions further modulate antitumor immunity, underscoring the complexity of this axis. Evidence indicates that neuronal signaling contributes not only to cancer-related symptoms, including pain, but also to treatment outcomes in chemotherapy, radiotherapy, and immunotherapy. Neural markers may serve as prognostic tools, while targeted modulation of neural transmission could enhance antitumor responses. However, the field faces significant challenges, including cellular diversity, spatiotemporal complexity, and limitations of animal models. Advances in molecular biology, bioinformatics, and interdisciplinary collaboration are essential to unravel these mechanisms. Exploring the neuro-immune-cancer axis holds promise for novel therapeutic strategies that integrate neuroscience, immunology, and oncology,aiming to improve both quality of life and survival in patients with cancer. Graphical Abstract

Cancer remains a formidable global health challenge, with therapeutic resistance and disease relapse frequently attributed to the persistence of a resilient subpopulation of cells known as cancer stem cells (CSCs). These cells, characterized by self-renewal capacity, continuous proliferation, and multi-lineage differentiation potential, drive tumorigenesis, metastasis, and evade conventional therapies. Traditional cancer treatments often fail to eradicate CSCs, leading to their enrichment post-therapy and subsequent tumor recurrence. This comprehensive review explores two innovative and interconnected therapeutic paradigms for targeting CSCs: ferroptosis and metabostemness. Ferroptosis, an iron-dependent form of regulated cell death distinct from apoptosis, offers a promising avenue to overcome apoptosis resistance prevalent in many cancers, including CSCs, by inducing lethal lipid peroxidation. Concurrently, “metabostemness” describes the unique metabolic reprogramming of CSCs, encompassing alterations in glucose, lipid, and amino acid metabolism, which are critical for maintaining their stemness, survival, and resistance to treatment. This review synthesizes the current understanding of the molecular mechanisms underlying ferroptosis and metabostemness in CSCs, highlighting emerging small-molecule strategies designed to exploit these vulnerabilities. The discussion includes direct ferroptosis inducers and compounds that sensitize CSCs to ferroptosis by disrupting their aberrant metabolic pathways. Furthermore, the synergistic potential of combining ferroptosis induction with metabolic inhibitors to enhance therapeutic efficacy and circumvent drug resistance is explored. Finally, the significant challenges in clinical translation, including issues of specificity, systemic toxicity, and tumor heterogeneity, are addressed, while proposing advanced drug delivery systems and integrated multi-omics approaches as crucial future directions for realizing the full potential of these novel anti-CSC strategies in precision oncology.

Glioblastoma (GBM) is the most aggressive and treatment-resistant form of primary brain tumor, characterized by rapid proliferation, extensive heterogeneity, and evasion of programmed cell death. Among emerging molecular regulators, microRNA-34 (miR-34) has gained attention as a potent tumor suppressor with the ability to modulate key signaling pathways involved in cell survival and death. This review explores the dual role of miR-34 in orchestrating apoptosis and autophagy, two fundamental processes that determine glioblastoma cell fate. We summarize current findings on how miR-34 directly targets genes involved in apoptotic signaling—such as BCL2, SIRT1, and NOTCH1—thereby promoting cell death and sensitizing GBM cells to therapeutic agents. Additionally, we highlight the context-dependent influence of miR-34 on autophagic flux, where it can either facilitate cytoprotective responses or trigger autophagy-associated cell death. Understanding this regulatory balance provides insight into the cellular plasticity of GBM and opens new avenues for therapeutic intervention. Targeting miR-34 or its downstream pathways offers promising potential to overcome resistance mechanisms and improve outcomes in glioblastoma treatment.