Aims: To identify plasma proteins associated with all-cause mortality and determine their relationships with chronic disease burden and biological aging at both the organismal and organ-specific levels, thereby providing insights into the biological mechanisms underlying healthy aging and longevity.

Methods: We conducted a prospective cohort study of 1,025 older adults from the LonGenity study, analyzing 4,265 plasma proteins. Associations between protein levels and all-cause mortality were evaluated using Cox proportional hazards regression over a mean follow-up of 8.05 years. Mortality-associated proteins were further examined for their relationships with chronic disease burden and proteome-derived measures of organismal and organ-specific biological aging. Findings were independently validated in 1,124 participants from the Baltimore Longitudinal Study of Aging (BLSA).

Results: Seventeen plasma proteins were significantly associated with all-cause mortality. Higher levels of Epidermal Growth Factor Receptor (ERBB1) and Anthrax Toxin Receptor 2 (ANTXR2) were associated with lower mortality risk and younger biological age across multiple organ systems. Conversely, higher levels of MIC-1 (GDF15), HE4, and IGFBP-2 were associated with increased mortality and older biological age across multiple organ systems. Specifically, elevated MIC-1 was associated with older organismal biological age, whereas ERBB1 was associated with younger liver biological age. These associations were independently replicated in the BLSA cohort.

Conclusion: Mortality-associated plasma proteins reflect key biological pathways involved in biological aging, physiological homeostasis, and systemic stress. These biomarkers may have potential utility for identifying individuals at increased mortality risk and advancing the development of biomarkers for healthy aging and longevity.

Lipoprotein(a) [Lp(a)] is a major, independent determinant of atherosclerotic cardiovascular disease and calcific aortic valve disease, yet its integration into routine clinical practice remains fragmented. Persistent uncertainties regarding when to measure Lp(a), how to interpret assay results, and how to manage elevated Lp(a) levels in the absence of approved Lp(a)-lowering therapies continue to hinder its adoption. Meanwhile, targeted therapies, including antisense oligonucleotides, siRNA agents, and small molecules, are advancing through phase 3 trials and may soon provide evidence regarding the clinical impact of pharmacological reduction of Lp(a). This evolving landscape demands a transition from passive awareness to active implementation. Early identification of individuals with elevated Lp(a), transparent communication of its clinical implications, and structured referral pathways between general practitioners and lipid clinics for the optimization of cardiovascular prevention and preparation for future therapeutic options, are crucial steps for bridging the existing Lp(a) gap. This perspective proposes a pragmatic framework for integrating Lp(a) into cardiovascular risk assessment and management across primary and specialist care, addressing operational challenges in measurement, interpretation, and treatment to support an actionable and coordinated Lp(a) clinical pathway. To this end, it formulates practical advice to orient Lp(a) management in primary care.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, is intricately linked with oxidative stress through shared regulatory nodes and reciprocal amplification loops. Although ferroptosis and oxidative stress have each been extensively investigated, their bidirectional crosstalk, together with its consequences for the tumor microenvironment, has yet to be systematically elucidated. On this basis, this review proposes and systematically dissects a “ferroptosis-oxidative stress-tumor microenvironment” triad, focusing on its bidirectional interaction network and therapeutic translational value. We analyze the driving mechanisms underlying the mutually amplifying loop between the two processes, including iron metabolism, lipid peroxidation cascades, antioxidant defense, and organelle function. Within the tumor microenvironment, this interplay drives context-dependent remodeling of immune cell function, cancer-associated fibroblast activity, angiogenesis, and tumor heterogeneity. Furthermore, this review evaluates emerging therapeutic strategies that target ferroptosis and oxidative stress within the TME, and outlines the obstacles hindering clinical translation and future directions. A deep understanding of the “ferroptosis-oxidative stress-tumor microenvironment” triad will advance our fundamental understanding of the execution and regulatory mechanisms of ferroptosis, and lay a theoretical foundation for the future development of precision therapeutic strategies centered on ferroptosis.

Cubic boron arsenide (BAs) is a promising filler for polymer-based thermal interface materials owing to its ultrahigh intrinsic thermal conductivity and electrically insulating nature. However, the interfacial thermal conductance (ITC) between BAs and polymer matrices has not been systematically quantified. Heat transport across BAs/epoxy interfaces was investigated by molecular dynamics simulations for five low-index surface terminations, and the calculated ITC varies by a factor of 1.72 among them. B-terminated interfaces systematically exhibit higher ITC than their As-terminated counterparts. The molecular functionalization of the surface shows that aminopropoxy functionalization at 16% coverage increases the ITC to 277 MW m^-2 K^-1, nearly twice that of the pristine B-terminated interface. Spectral analysis indicates that surface-bound functional groups act as vibrational bridges between BAs and epoxy, while covalent cross-linking with the epoxy network further strengthens the existing interfacial heat-transfer channels. The area-normalized interfacial coupling stiffness reveals that the termination dependence of ITC is governed by the strength of the cross-interface vibrational coupling. This work provides systematic quantitative data for Bas/polymer interfaces and shows that surface termination control and covalent functionalization can be combined to improve interfacial thermal conductance.

Hibernation is one of nature’s most remarkable examples of reversible physiological adaptation, yet its potential to inform geroscience remains underexplored. Lifespan patterns in hibernators are not fully explained by allometric scaling, as hibernators can outlive non-hibernating species of comparable body size. It is further characterized by the preservation of tissue function and integrity despite marked calorie restriction, inactivity, and hypometabolism. In this review, we examine the hibernation phenotype as a naturally evolved program of biological maintenance that may limit the accumulation of age-related molecular and cellular damage. We first discuss the relationship between hibernation, longevity, and life-history evolution before reviewing evidence that hibernation modulates multiple hallmarks of ageing through integrated regulation of metabolism, mitochondrial maintenance, proteostasis, nutrient sensing, endocrine signaling, immune function, and epigenetic remodeling. We further highlight emerging observations associating hibernation with telomere maintenance and slower epigenetic ageing, while emphasizing the key knowledge gaps that remain regarding the causal relationship between the phenotype of hibernation and slower ageing, cellular senescence, genome maintenance, and age-dependent changes in hibernation expression. Finally, we discuss how comparative biology, multi-omics approaches, and functional biomarkers of aging throughout the different phases of hibernation (before, at the onset, during, and after torpor) may help identify evolutionarily conserved protective mechanisms that can be translated into novel strategies to promote healthy human aging from a bioinspired perspective. This Review was developed following discussions initiated during the September 2025 NSF Quantitative Approaches and Understudied Questions in the Biology of Aging Workshop (Paris, France).

There is a growing demand from society for gerotherapeutic interventions that can extend healthspan. Yet the increasing commercialization of insufficiently validated gerotherapeutics, threatens to undermine the public confidence and the responsible translation of healthy longevity research into practice. The Unlock Healthy Longevity Conference 2026 convened international experts in Singapore to exchange scientific advances in precision geromedicine, with a particular focus on nutraceuticals and repurposed drugs. Precision geromedicine is increasingly being translated into clinical settings; however, standardized frameworks for clinical evaluation, implementation, quality assurance, and oversight remain insufficiently established. This emerging paradigm emphasises the need for collaboration across multiple stakeholders to support the development of a robust, safe, scalable, and equitable ecosystem. A central theme across the sessions was the need to advance clinical human validation, translation, and the development of standards and clinical guidelines. Panel discussions converged on the importance of developing robust clinical and data infrastructures to generate reproducible evidence capable of informing real-world clinical practice and enable equitable access to healthy longevity. Presentations addressed emerging clinical biomarkers of ageing and data-driven approaches to guide gerotherapeutics, including changes in DNA methylation and skin and gut as organ-level readouts of biological ageing. Several potential candidate gerotherapeutics were discussed, including the nutraceutical compounds urolithin A and ergothioneine, and repurposed drugs such as glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitor. Additional sessions explored the clinical implementation of gerotherapeutics taking into account ethical, safety, and regulatory considerations. This report summarises the key messages and research priorities presented at the conference.

Electrochromic (EC) glazing can regulate solar heat gain, but the control signal affects the balance between cooling and heating energy use. This study compares the Load strategy, which uses predicted sensible load, with the fixed temperature-based T24 strategy, which uses a 24 °C upper switching threshold. Both strategies were implemented through the EnergyPlus Energy Management System (EMS) under identical building, heating, ventilation, and air-conditioning (HVAC), thermostat, weather, and EC glazing conditions across 384 worldwide EnergyPlus Weather (EPW) records. EC (Load) reduced cooling electricity across most climates but increased heating gas use, with larger penalties in colder regions. The resulting annual energy-use intensity (EUI) was 146.54 kWh m^-2 year^-1 for EC (Load) and 145.23 kWh m^-2 year^-1 for EC (T24), while the carbon-equivalent response varied geographically because of the competing electricity and heating effects. These results indicate that the Load strategy primarily redistributes energy use between cooling and heating rather than providing a universal annual-energy advantage, thereby demonstrating the climate-dependent energy trade-offs associated with this strategy.

Metal-organic frameworks (MOFs) have emerged as a versatile class of porous nanomaterials for cancer therapy owing to their programmable compositions, ordered architectures, and multifunctional properties. Among them, meso-tetra(4-carboxyphenyl) porphyrin (TCPP)-based MOFs have attracted particular attention because the porphyrinic ligand serves not only as a structural building block but also as an intrinsic photosensitizer and sonosensitizer, while framework metal nodes provide catalytic, imaging, and radiosensitizing functions. The synergistic integration of these components enables TCPP-based MOFs to function as multifunctional theranostic platforms rather than conventional drug carriers. In this Perspective, we organize recent advances around a structure–active center–mechanism–therapeutic outcome framework for interpreting TCPP-based MOFs in cancer theranostics. We first discuss the coordination chemistry of TCPP, representative framework topologies, and the distinct roles of metalloporphyrin centers and framework metal nodes in regulating reactive oxygen species generation, catalytic activity, ferroptosis, and multimodal imaging. We then use this framework to examine their applications in photodynamic, chemodynamic, sonodynamic, radiotherapy/radiosensitization, and radiodynamic strategies, as well as drug-delivery-enabled combination therapy and image-guided theranostics. Finally, we highlight current challenges associated with biosafety, degradation, scalable synthesis, and biological barriers, and outline future opportunities for developing structurally programmable, stimulus-responsive, and clinically translatable TCPP-based MOFs for precision oncology.

Glioblastoma (GBM) is the most lethal primary brain tumor, with minimal therapeutic progress over the past two decades. A defining feature of GBM is its intrinsic resistance to apoptosis, prompting interest in activating alternative cell death pathways such as ferroptosis, an iron-dependent process driven by lipid peroxidation. In GBM, ferroptosis represents a context-dependent vulnerability that arises directly from tumor specific lipid metabolic reprogramming. Here, we outline a unifying framework in which ferroptosis sensitivity is governed by three interdependent axes: availability of oxidizable lipids, redox buffering, and iron handling. Genetic alterations common in GBM, such as CDKN2A loss, EGFR amplification or mutation, and PTEN loss, reshape these axes to either suppress or promote ferroptotic cell death. This susceptibility is further modulated by cellular state and the tumor microenvironment. Effective therapeutic targeting will require biomarker-driven patient stratification, rational combination strategies, and the development of brain-penetrant agents with tumor-selective activity. Together, this framework positions ferroptosis not as a universally inducible death pathway in GBM, but as a context-dependent vulnerability that can be therapeutically exploited in tumors already poised near the ferroptosis threshold.

This review summarizes the research progress on bone adhesives as alternatives to traditional metal internal fixation, highlighting the differences in microenvironment and structure among bones with different bone qualities, which necessitate a shift from universal to personalized adhesive design. The article outlines four key clinical objectives: rapid and robust adhesion, sufficient adhesive and cohesive strength, adjustable degradation and good biocompatibility, biological promotion and microenvironment modulation. It evaluates systems such as cyanoacrylate, calcium phosphate cement, and biomimetic composite hydrogels, while analyzing adhesion mechanisms like catechol-mediated and phosphate-calcium coordination. For different bone qualities and anatomical sites, differentiated design strategies are proposed, emphasizing the synergistic optimization of adhesive chemistry, mechanical behavior, degradation, and bioactivity. This review provides direction for the development and clinical translation of next-generation bone adhesives.

Ferroptosis is an iron-dependent form of regulated cell death driven by the lethal accumulation of lipid peroxides. Accumulating evidence indicates that the extracellular landscape, the acellular functional subset of the tumor microenvironment (TME) comprising the extracellular matrix, soluble metabolites, cytokines, extracellular vesicles (EVs), and physicochemical conditions such as pH and oxygen content, actively determine cellular susceptibility to ferroptosis. Extracellular nutrients, acidic and hypoxic conditions modulate intracellular redox homeostasis, while ferroptosis-related signals are transmitted between cells through EVs, cytokines, and metabolites. Ferroptosis in turn bidirectionally shapes anti-tumor immunity, acting as immunogenic cell death yet also releasing immunosuppressive mediators that impair T cells. This review summarizes the canonical intracellular mechanisms of ferroptosis, highlights the bidirectional crosstalk between cells and the extracellular landscape, and discusses therapeutic strategies targeting this landscape, including reshaping nutrient availability, engineering EV-based delivery systems, and designing microenvironment-responsive nanomaterials. Key limitations of the field and perspectives are also outlined for safe and effective ferroptosis-based anti-tumor therapies.

Histology has long served as the foundation of tissue diagnosis, yet its reliance on thin 2D sections incompletely captures the spatial continuity, volumetric heterogeneity, and multicellular architecture of biological tissues. Recent advances in volumetric imaging, spatial omics, label-free optical pathology, and artificial intelligence are enabling tissue analysis beyond the conventional glass slide. In this Perspective, we discuss the emergence of 3D histology and the technological developments driving the transition from planar sampling to volumetric tissue analysis. We highlight how the added spatial dimension can reveal diagnostically relevant features that are only partially represented in conventional sections, and discuss efforts to extend molecular profiling into intact tissues through multiplexed imaging and volumetric spatial omics. We further examine the growing role of label-free modalities, particularly stimulated Raman scattering microscopy, for rapid and minimally destructive pathology. Finally, we consider the computational foundations required to reconstruct, align and interpret volumetric data, including emerging applications in virtual histology and molecular prediction. Together, these developments suggest that 3D histology is evolving into a broader framework for integrating tissue morphology, molecular state, and function within intact spatial contexts, with emerging opportunities for biological discovery and precision medicine.

Advanced age is associated with immune decline and remodeling, including loss of adaptive reserve, impaired host defense, and chronic low-grade inflammation. Yet the immune phenotype of long-lived individuals (LLIs), especially centenarians, shows that immune aging is not a uniform process. Rather than reflecting global rejuvenation, longevity-associated immunity is better understood as selective preservation of immune competence, with selected cellular features retaining youth-like characteristics under the constraints of extreme age. The most direct cellular evidence comes from innate effector functions, including preserved natural killer (NK)-cell cytotoxic surveillance and neutrophil chemotaxis, phagocytosis, and redox control. T-cell findings are more heterogeneous, including maintenance of a non-inverted CD4/CD8 ratio and partial naive CD4⁺ T-cell reserve, while T helper 17 cell (Th17)/regulatory T cell (Treg) data provide more limited support for preserved regulatory-inflammatory balance. Myeloid and antigen-presenting-cell programs may further support clearance and antigen handling, although direct functional evidence remains more limited. Molecular studies point to candidate support layers rather than proven causal mechanisms, including coordinated immune-cell states and communication, survival and apoptosis-regulatory programs, ribosome-inflammation balance, autophagy-lysosomal and mitochondrial quality control, and buffering of inflammatory and senescence-associated signals. Importantly, some immune changes reported in LLIs fall outside the youth-like frame: cytotoxic and effector-memory T-cell states and repertoire remodeling, humoral shifts, and complement changes are better interpreted as adaptive remodeling whose occurrence and significance depend on lifelong immunological experience. This framework places selective preservation of immune competence at the center of LLI immune biology while distinguishing it from experience-shaped adaptive remodeling.

Aims: Smartphone Augmented Reality (AR) enables social applications, but single-point Inverse Kinematics (IK) avatar tracking limits pose expressiveness and introduces positional errors. We introduce DPIK, a dual-point tracking system combining hand IK with face tracking, and evaluated whether it improves tracking accuracy, embodiment, and user experience over single-point IK.

Methods: DPIK uses the front and back cameras of ARKit to track the face of the user and hand/device pose, driving avatar hand IK and hip/head positioning. In a within-subjects study (N=20), we compared DPIK against our prior single-point IK system (ARIKA) and full-body motion capture (ground truth) across positional/rotational accuracy, embodiment, and user experience. We also examined temporal drift in tracking error and Spearman correlations between error and embodiment/user experience scores.

Results: DPIK significantly outperformed ARIKA in positional accuracy for 18 of 19 joints and reduced head rotational error by over . A temporal drift analysis found that neither ARIKA nor DPIK exhibited statistically significant growth in positional error over time. DPIK received significantly higher overall user experience ratings than ARIKA. Embodiment differences were not statistically significant, though effect sizes were moderate-to-large. Exploratory correlations suggested lower DPIK embodiment scores for Acceptance and Control with higher positional error, but these did not survive multiple-comparison correction; positional error did not predict user experience ratings for either technique.

Conclusion: DPIK improves tracking accuracy and user experience over ARIKA, with tracking fidelity selectively shaping embodiment rather than overall user experience, highlighting a distinction between perceptual ownership and holistic evaluation of smartphone AR avatar systems.

Aims: Ferroptosis, an iron-dependent form of regulated cell death, contributes to neuronal injury after ischemic stroke. Because our previous cancer-cell screens identified ataxia-telangiectasia mutated (ATM) kinase, as a ferroptosis regulator, we investigated whether ATM inhibition protects neural tissue after ischemic stroke and examined determinants of therapeutic response.

Methods: ATM inhibitors, including the brain-penetrant clinical compound AZD1390, were evaluated in cultured cancer and neuronal cells, oxygen-glucose-deprived rat and mouse brain slices, and permanent middle cerebral artery occlusion models using multiple inbred and Rabep2-genotype mouse strains. Cell viability, cytotoxicity, lipid peroxidation, ferroptosis-associated markers, infarct volume, and collateral vessel density were assessed. Topical AZD1390 was also tested in mice with impaired collateral networks.

Results: ATM inhibition reduced ferroptosis-associated lipid oxidative injury and protected neurons in multiple preclinical stroke models. AZD1390 decreased lipid peroxidation and neuronal death, and reduced infarct volume in B6/J and B6/NJ mice, but not in BALB mice. Treatment efficacy varied among strains and was correlated with collateral vascular density. Systemic AZD1390 was likewise ineffective in Rabep2-knockout mice with deficient collateral networks. Early topical administration also reduced infarct volume in mice with limited collateral networks; however, differences in treatment timing and route preclude direct attribution to improved local drug delivery.

Conclusion: ATM inhibition may attenuate ferroptosis-associated neuronal injury after ischemic stroke, while collateral vascular anatomy may influence therapeutic response. These findings support further mechanistic and translational evaluation of ferroptosis-targeting strategies in stroke.

Pancreatic cancer is a highly aggressive and lethal malignancy with an exceptionally poor prognosis. Its clinical management is severely hampered by insidious early symptoms, strong invasiveness, intrinsic chemoresistance, and limited efficacy of conventional therapies. Carbon dots (CDs) have shown great promise in precision cancer theranostics owing to their excellent optical properties, high biocompatibility, controlled drug loading and release capabilities and customizable targeting features. This review critically examines the major therapeutic barriers in pancreatic cancer management, systematically summarizes the applications of CDs in pancreatic cancer imaging, targeted drug delivery, hyperthermia and pH-responsive theranostics, analyzes the current limitations of CD-based nanosystems, and discusses future development directions. This work aims to provide a rigorous theoretical foundation for the rational design and development of novel CD-mediated precision intervention strategies for pancreatic cancer.

Aims: Circular RNAs (circRNAs) act as vital microRNA (miRNA) sponges and participate in the pathogenesis of various complex diseases. Most existing computational methods focus on sequence-level prediction of circRNA-miRNA interactions, while few tools can accurately locate interaction sites at the nucleotide level.

Methods: In this study, we propose CMIFCG, a novel model combining fully convolutional neural networks (FCNs) and bidirectional gated recurrent units (BiGRU) for nucleotide-level prediction of circRNA-miRNA interaction sites. We adopted one-hot encoding for sequence preprocessing, utilized stacked convolutional modules to extract high-order features, and integrated BiGRU to capture sequential association features. The decoding module with skip connections restores feature maps to the original sequence size for precise site prediction. We constructed four datasets with different sequence lengths and negative samples to evaluate model performance.

Results: Experimental results show that CMIFCG achieves better performance than other baseline models, and excessive module stacking causes performance degradation. Motif analysis confirms that the predicted motifs match well with known miRNA sequences. Partial predicted interactions are further verified via public databases.

Conclusion: In summary, the CMIFCG model enables effective fine-grained identification of circRNA-miRNA interaction sites, providing a new tool for exploring circRNA regulatory mechanisms and disease-related molecular pathways.

Proton exchange membrane water electrolysis (PEMWE) is regarded as a practical hydrogen production method due to its advantages such as smaller resistance loss, higher current density, and higher hydrogen purity. However, the efficiency of PEMWE technology is severely hindered by the slow kinetics and the high reaction barrier of the oxygen evolution reaction (OER). Therefore, developing cost-effective, efficient, and stable OER electrocatalysts is urgently needed. The RuO₂-based elec-trocatalysts have been proven to be promising alternatives to Ir-based catalysts due to their excellent electrocatalytic activity and high adaptability in acidic environ-ments. This review comprehensively summarizes and discusses the morphological control strategies, advanced modification strategies, and structural synergy of RuO₂ catalysts. Furthermore, the composition and industrial development status of PEMWE are elaborated, along with the current research progress of RuO₂ as an an-ode in electrolysis. Finally, relevant suggestions for RuO₂ research and practical ap-plications are presented, the challenges facing practical deployment are analyzed, and future research directions are outlined.

DNA replication constantly faces obstacles that threaten genome stability. Faithful duplication requires replication forks to smoothly process template damage, chemical or topological blocks, and repair intermediates. Traditionally, replication-associated lesions are described by their initial structures (nicks, gaps, etc.). However, their S-phase identities are highly transitional: a template single-strand break (SSB) can become a one-ended double-strand break (DSB) upon fork arrival, a replication fork stalled by a template block can reverse, restart, or collapse, and a repriming event leaves a post-replicative single-stranded DNA (ssDNA) gap. The biological consequence of a lesion depends heavily on its structural transitions and how it is “routed” through distinct repair, bypass, or cleavage pathways. In this review, we shift our focus from static structural identities to dynamic lesion routing, emphasizing the coordination between SSB repair (SSBR) and DSB repair (DSBR). We first summarize the major sources of replication-associated strand lesions, and then discuss how strand lesions are managed across three processing windows: SSBR before fork encounter, the overlap zone in which gaps and stressed forks can be buffered without immediate DSB conversion, and broken-fork/DSBR-centered processing after DSB formation, including homologous recombination (HR)-mediated restart, break-induced replication (BIR)-like synthesis, or end joining. Depending on the routing network, lesion processing can result in accurate completion, delayed resolution or salvage, mutagenic completion, structural genome scars, or cytotoxic genome instability. Finally, we discuss how this dynamic framework refines our understanding of DNA damage response (DDR)-targeted cancer therapies, drug resistance, and treatment outcomes in different genetic or therapeutic contexts.

DNA replication and transcription operate on the same chromatin template and inevitably interfere with one another, giving rise to transcription-replication conflicts (TRCs), an important endogenous source of replication stress and genome instability. Although head-on (HO) conflicts are generally more disruptive than co-directional (CD) encounters, orientation alone does not determine the outcome. Gene architecture, transcriptional activity, replication timing, chromatin environment, DNA topology, and R-loop dynamics can all influence whether an approaching replication fork pauses, collapses, or traverses a transcribed region. Recent single-molecule, genomic, and biochemical studies further suggest that some CD encounters can be traversed under favorable topological and transcriptional conditions, although the mechanisms that permit such bypass and their broader biological significance remain incompletely understood. Here, we discuss TRC control within an operational framework comprising prevention, resolution, tolerance, and recovery. We examine how cells coordinate replication and transcription in space and time, regulate R-loop formation and turnover, protect or remodel challenged forks and chromatin, and modify or remove transcription complexes at conflict sites. We also consider how emerging single-molecule and multi-omic approaches can distinguish transient fork pausing from persistent pathological conflicts. Finally, we discuss the contributions of TRCs to cancer-associated chromosomal instability, cellular senescence, and neurodegenerative disease, and highlight the questions that must be resolved to understand how cells preserve genome integrity when replication and transcription compete for the same DNA template.

Aims: Ferroptosis is a form of cell death associated with uncontrolled lipid peroxidation of polyunsaturated fatty acids (PUFAs) leading to membrane destruction. We previously showed that dietary dihomo-gamma-linolenic acid (DGLA) induces ferroptosis in Caenorhabditis elegans germ cells in a dose-dependent manner, and that the sensitivity of germ cells to dietary DGLA is altered by many genetic, dietary, and chemical interventions.

Methods: The severity of germ cell death was documented after dietary supplementation of DGLA, vitamin B12, methionine, and choline to wild type and mutant Caenorhabditis elegans (C. elegans). The presence of germ cells, gametes, and embryos was visualized in young adult worms with 4′,6-diamidino-2-phenylindole (DAPI).

Results: The addition of vitamin B12 rescued DGLA-induced cell death. For this protection, vitamin B12 functions as a cofactor for methionine synthase (METR-1). In addition, dietary methionine and choline rescued germ cell death in the context of low-B12 diets as well as in ferroptosis-sensitive metr-1 and sams-1 mutant strains. The pcyt-1 mutant worms, with reduced capacity for phosphatidylcholine (PC) synthesis, were not responsive to dietary vitamin B12-mediated rescue of DGLA-induced ferroptosis, providing evidence that PC synthesis and homeostasis play key roles in ferroptosis susceptibility. Oleic acid supplementation rescues DGLA-induced cell death in wild type, but not in pcyt-1 mutant strains.

Conclusion: These studies reveal the requirement for dietary vitamin B12 and sufficient PC synthesis in protection from dietary DGLA-induced ferroptosis, highlighting the importance of phospholipid metabolism in ferroptosis regulation.

Ferroptosis is an iron-dependent form of regulated cell death that has attracted considerable attention as a promising therapeutic strategy because of its ability to eliminate tumor cells. However, tumors are multicellular ecosystems in which malignant cells coexist with diverse stromal and immune cell populations that critically shape tumor progression, anti-tumor immunity, and therapeutic responses. Emerging evidence indicates that ferroptosis exerts fundamentally distinct biological effects across these non-malignant cell populations, extending far beyond direct tumor cell killing. In this review, we propose a cell type-centered conceptual framework in which the consequences of ferroptosis are determined primarily by cellular context rather than by ferroptosis itself. While ferroptosis resistance enables certain cell types, such as fibroblasts and macrophages, within the tumor microenvironment (TME) to maintain tumor-promoting functions, ferroptosis compromises the persistence and effector activity of cytotoxic lymphocytes, including CD8⁺ T cells and natural killer cells. Conversely, ferroptosis in neutrophils and polymorphonuclear myeloid-derived suppressor cells may generate oxidized lipid mediators that paradoxically reinforce immune suppression despite reducing cell abundance. Therefore, in this review, we integrate recent advances in understanding ferroptosis across major nonmalignant cell populations within the TME, focusing on its effects on cell fate, functional plasticity, and anti-tumor immunity. We further discuss how these insights may guide the development of precision ferroptosis-based therapies that selectively target tumor-promoting cell states while preserving protective immune responses.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Its execution depends not only on the amount of lipid peroxides, but also on where oxidizable lipids, redox-active iron, reactive oxygen species, and antioxidant defenses are distributed within cells. This review summarizes current evidence for organelle-resolved regulation of ferroptosis and oxidative stress, with emphasis on the endoplasmic reticulum, peroxisomes, mitochondria, lysosomes, lipid droplets, and phase-separated condensates. We discuss how lipid remodeling, ether lipid synthesis, mitochondrial metabolism and local antioxidant defense, ferritinophagy, lysosomal lipid peroxidation, and lipid droplet-mediated fatty acid buffering influence ferroptosis sensitivity. We also summarize how organelle-specific redox defenses and stress-adaptive signaling pathways may shape therapeutic responses. Together, these studies show that ferroptosis is regulated by coordinated changes in lipid metabolism, iron handling, and antioxidant capacity across distinct subcellular compartments.

The tumor immune microenvironment (TIME) is a principal determinant of tumor progression, metastatic dissemination, and therapeutic response. Cellular senescence, primarily through the senescence-associated secretory phenotype (SASP), progressively reshapes the TIME toward immunosuppressive and therapy-resistant states. Here, we propose an integrative framework of “senescence-associated transcriptional reprogramming” comprising three mechanistic layers: endogenous inflammation-driven signaling centered on the cGAS-STING-NF-κB-IFN hub; lineage-specific epigenetic lock-in in immune cells; and metabolic-epigenetic coupling. We further discuss mechanism-guided, temporally optimized senolytic and senomorphic strategies, particularly relevant to elderly cancer patients, to rationally reverse senescence-driven tumor immune tolerance and enhance current immunotherapies.

Aims: Severe coronavirus disease 2019 (COVID-19) is characterized by marked heterogeneity in lung pathology, including diffuse alveolar damage, inflammation, and fibrosis. However, how spatially organized cellular interactions contribute to these divergent pathological outcomes remains incompletely understood. We aimed to define the spatial organization of cellular microenvironments in severe COVID-19 lungs and identify niche-specific cellular interactions associated with distinct histopathological states.

Methods: We applied imaging-based single-cell spatial transcriptomics to post-mortem lung tissues from patients with severe COVID-19 and control subjects, enabling high-resolution mapping of cellular composition, spatial neighborhoods, and predicted ligand-receptor interactions within intact tissue architecture.

Results: Analysis of 76,973 cells identified 20 distinct cell populations and revealed marked heterogeneity between COVID-19 samples, corresponding to different histopathological states. Spatial niche analysis identified discrete macrophage-associated microenvironments. Fibrotic niches were enriched in chitinase 3-like 1 (CHI3L1)/matrix metalloproteinase 9 (MMP9^hi) macrophages spatially associated with collagen type I alpha 1 chain (COL1A1⁺) fibroblasts and basal cells. Ligand-receptor inference predicted macrophage-derived transforming growth factor beta (TGF-β) and galectin-3 signaling as drivers of pathogenic fibroblast activation and extracellular matrix remodeling. In contrast, alveolar niches contained secreted phosphoprotein 1 (SPP1^hi) macrophages exposed to epithelial-derived cues, including WNT ligands and granulocyte-macrophage colony-stimulating factor (GM-CSF), consistent with differentiation toward an alveolar macrophage-like state.

Conclusion: Severe COVID-19 lungs are organized into distinct spatial niches associated with divergent immunopathological trajectories. Imaging-based spatial transcriptomics provides a platform to link histopathological states with localized cellular interactions and macrophage-driven tissue remodeling programs.