bims-cagime 2026-04-12 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–04–12
thirty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

PHGDH is a targetable driver of PDAC progression.
Ferroptosis as an approach to leverage cancer metabolism.
Neutral lipid quality control gates ferroptotic cell death.
Systematic Evaluation Defines the Limits of Ferroptosis in Cancer Therapy.
Inflammatory memory disables a DDR1 degradation checkpoint to enable pancreatic cancer growth.
Polyunsaturated lipids kill senescent cells by ferroptosis.
Baseline cellular state dictates the molecular impact of KRAS mutant variants in pancreatic cancer cells.
Lysosomal rupture: An emerging switch for collective ferroptosis.
Pancreatic Cancer Interception with RAS Inhibition Improves Survival.
Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.
Amoeboid-mesenchymal transition and the proteolytic control of cancer invasion plasticity.
Membrane integrity control - from lipids to proteins and back to lipids.
Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.
Ten questions on membrane biophysics.
Coupling between sterol and sphingolipid structure in ordered membrane domains.
Phase separation across membranes and condensates in cell organization and function.
A feedback loop between cell proliferation and ROS regulates ferroptosis sensitivity.
Immunoferroptosis: ferroptosis meets tumor immunity and immunotherapy.
Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.
Translation in proximity to forming autophagosomes during sustained autophagy.
NCOA4-mediated ferritinophagy: emerging role and novel therapeutic target in precision oncology.
Epithelial-Fibroblast Crosstalk Supports Early Tumorigenesis.
OncoRisk: a state-of-the-art web server for bridging the oncogenic databases and pan-cancer cohorts to the translational oncology.
Fibroblast-Specific GPX4 Deletion Exacerbates IBD via Lipid Peroxidation.
Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.
AQuA2-Cloud: a web platform for fluorescence bioimaging activity analysis.
Vitamin C slows primate aging by targeting iron-driven lipid peroxidation.
NucleoNet and DropNet: Generalist deep learning models for instance segmentation of nuclei and lipid droplets from electron microscopy images.
Hypoxia-induced XBP1s-MYDGF axis suppresses ferroptosis through UBQLN1-mediated stabilization of LCN2 in gastric cancer.
Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF.
Epstein-Barr Virus Latent Membrane Protein 1 Suppresses Ferroptosis via Pentose Phosphate Pathway and Glutathione Metabolism.

bioRxiv. 2026 Mar 14. pii: 2026.03.11.711147. [Epub ahead of print]

PHGDH is a targetable driver of PDAC progression.

Yumi Kim, Le Jin Sun, Meredith Long, Samantha Caldwell, H Carlo Maurer, Kenneth P Olive, Florian Karreth, Gina M DeNicola.

Pancreatic ductal adenocarcinoma (PDAC) arises in a nutrient-deprived microenvironment through progressive stages from pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma. While serine metabolism supports tumor growth across multiple cancer types, the stage-specific role of de novo serine synthesis in PDAC evolution remains undefined. Here, we show that expression of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of serine biosynthesis, increases progressively from PanIN to invasive PDAC in human and mouse specimens. Using genetically engineered mouse models with inducible PHGDH knockdown, we found that PHGDH loss delayed PDAC development. Unexpectedly, PHGDH-deficient tumors did not increase reliance on exogenous serine, and dietary serine/glycine manipulation had no effect on tumor development. Instead, stable isotope tracing and metabolomic profiling revealed that PHGDH loss suppressed mTOR signaling, reduced expression of the glutamine transporter ASCT2, and impaired glutamine uptake and utilization. Leveraging this metabolic liability, we demonstrated that PHGDH-deficient tumors exhibited selective sensitivity to the glutamine antagonist DRP-104, whereas PHGDH-intact tumors were resistant. These findings reveal an unanticipated connection between serine biosynthesis and glutamine metabolism in PDAC and identify a therapeutic vulnerability that may be exploited through combined metabolic targeting.
Statement of significance: PHGDH supports PDAC progression not primarily through serine provision, but by maintaining glutamine metabolism and mTOR signaling. This unanticipated metabolic crosstalk creates a synthetic lethal vulnerability to glutamine antagonism in PHGDH-deficient tumors, providing a rationale for combining serine synthesis pathway inhibitors with glutamine-targeting therapies in pancreatic cancer.

DOI: https://doi.org/10.64898/2026.03.11.711147
Trends Cell Biol. 2026 Apr 09. pii: S0962-8924(26)00039-5. [Epub ahead of print]

Ferroptosis as an approach to leverage cancer metabolism.

Jenny Jin, Jiachen Hu, Mingyue Li, Wei Gu, Xuejun Jiang, Brent R Stockwell.

  Ferroptosis is a cell death process defined by the iron-mediated peroxidation of membrane phospholipids that overwhelms the cell's innate antioxidant capabilities. Sitting at the nexus of iron, lipid, reactive oxygen species stress responses, and cellular metabolism, ferroptosis is intricately tied to these pathways. The burgeoning field of cancer metabolism has revealed that cancer cells exhibit changes in ferroptosis-relevant metabolic pathways, thereby opening an important avenue of investigation into whether tumors can have characteristic metabolic alterations that render them exquisitely sensitive to ferroptotic cell death. In this review, we highlight recent findings in the metabolic pathways linking ferroptosis and oncogenesis, as well as implications for future cancer therapeutic strategies.

Keywords:  cancer metabolism; ferroptosis; lipid metabolism; lipidomics; metabolomics; oncogenic signaling

DOI:  https://doi.org/10.1016/j.tcb.2026.03.008
Trends Cell Biol. 2026 Apr 08. pii: S0962-8924(26)00042-5. [Epub ahead of print]

Neutral lipid quality control gates ferroptotic cell death.

Hui Zhang, Xiaojun Cai, Quazi T H Shubhra.

  By uncovering a lipid droplet (LD) quality-control pathway driven by ferroptosis suppressor protein 1, Lange et al. show that neutral-lipid oxidation shapes ferroptosis vulnerability. This work expands ferroptosis regulation beyond membrane phospholipids and positions LDs as active redox control sites with broad implications for cell fate regulation.

Keywords:  Cell death regulation; Ferroptosis; Lipid droplets; Neutral lipid metabolism; Organelle-specific redox control

DOI:  https://doi.org/10.1016/j.tcb.2026.03.011
bioRxiv. 2026 Mar 14. pii: 2026.03.11.711115. [Epub ahead of print]

Systematic Evaluation Defines the Limits of Ferroptosis in Cancer Therapy.

Kenji M Fujihara, Azmi Aziz, Behnia Akbari, Maria Gutierrez-Perez, Gregory Francis, Siham Zentout, Kameng Wu, Nicholas J Clemons, Erdem M Terzi, Michael E Pacold, Richard Possemato.

Ferroptosis is a cell death mechanism characterized by the accumulation of iron-catalyzed lipid peroxides in membrane lipid acyl chains and subsequent loss of membrane integrity. 1 Despite thorough investigation of its mechanisms in cultured cells, induction of ferroptosis has unresolved clinical utility in cancer therapy. Here, we systematically evaluate ferroptosis induction via multiple mechanisms, in both cell and tumor models, using focused genetic screens, genetic loss-of-function systems, and pharmacological perturbations. Through this analysis we identify cancer cell line subsets with distinct responses to canonical ferroptosis inducers and suppressors and define the underpinnings of each. Inhibition of central in vitro ferroptosis suppressors GPX4, GCLC, or SLC7A11 across these multiple models fails to impact established tumor growth. In contrast, deficiency in the cytosolic thioredoxin reductase and pharmacologic GCLC inhibition potently induces tumor regression and triggers a form of non-ferroptotic cell death regulated by cystine availability and translation. These analyses further reveal that the principal essential function of environmental cystine in cultured cells is to support selenoprotein function, identified through investigating our finding that β-mercaptoethanol supports exponential growth in cystine-free conditions. Thus, while ferroptosis activation may be efficacious alone or in combination with other therapies in specific tumor contexts, cell culture systems greatly overestimate the potential anti-cancer effects of ferroptosis induction via the GPX4 axis.

DOI: https://doi.org/10.64898/2026.03.11.711115
bioRxiv. 2026 Apr 03. pii: 2026.04.01.715820. [Epub ahead of print]

Inflammatory memory disables a DDR1 degradation checkpoint to enable pancreatic cancer growth.

Fei Yang, Bo Lin, Zihang Yuan, Yongkang Yuan, Xiaohong Pu, Chunlan Wang, Kosuke Watari, Rongkui Luo, Beicheng Sun, Michael Karin, Hua Su.

Inflammation and stroma remodeling regulate pancreatic ductal adenocarcinoma (PDAC), but how or if these cues are integrated at the molecular level remains unclear. Here, we identify a metabolic checkpoint that controls the stability of the collagen receptor DDR1, and subsequent tumorigenesis. We show that defective Col-I remodeling deprives PDAC cells of the high affinity DDR1 ligand, ¾Col-I, resulting in reduced ATP and activation of AMPK. AMPK phosphorylates DDR1 at T519, promoting its recognition by the E3 ubiquitin ligase adaptor FBXW2 and subsequent degradation. Importantly, this degradation pathway can be disabled by inflammatory signaling. Exposure to inflammatory cytokines induces methylation-dependent silencing of FBXW2, which establishes an inflammatory memory that preserves DDR1 stability, enabling sustained ligand-triggered receptor oligomerization and downstream NF-κB-NRF2 signaling even in restrictive stromal environments. Together, these findings identify regulated receptor turnover as a mechanism through which stromal architecture, metabolic state, and inflammatory memory are integrated to control PDAC progression.

DOI: https://doi.org/10.64898/2026.04.01.715820
Cell Metab. 2026 Apr 07. pii: S1550-4131(26)00094-X. [Epub ahead of print]38(4): 643-644

Polyunsaturated lipids kill senescent cells by ferroptosis.

Mariantonietta D'Ambrosio, Jesús Gil.

In a recent Cell Press Blue paper, Zhang et al. identify two polyunsaturated lipids that selectively eliminate senescent cells by inducing ferroptosis, uncovering this iron-dependent cell death pathway as a vulnerability for senescent cells. Their findings position ferroptosis induction as a promising strategy for targeting senescence and aging-associated diseases.

DOI: https://doi.org/10.1016/j.cmet.2026.02.021
bioRxiv. 2026 Mar 12. pii: 2026.03.10.710185. [Epub ahead of print]

Baseline cellular state dictates the molecular impact of KRAS mutant variants in pancreatic cancer cells.

Yanixa Quiñones-Avilés, Barbora Salovska, Cassandra S Markham, Yi Di, Benjamin E Turk, Yansheng Liu, Mandar Deepak Muzumdar.

KRAS is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), where hotspot alterations in codons 12, 13, and 61 drive tumor initiation and progression. Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signaling programs in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation. Comparisons with established KRAS reference signatures revealed significant but moderate overlap at the mRNA level and less so at the proteome level. Pathway analyses highlighted interferon response and mitochondrial translation as recurrently altered across alleles, while phosphoproteomic data confirmed robust ERK1/2 activity and suppression of DYRK kinase substrates by mutant KRAS expression. Importantly, no robust allele-specific molecular programs were identified. Together, our study establishes a comprehensive multi-omics resource for KRAS signaling in PDAC and demonstrates that cellular context exerts a stronger influence than allele identity in shaping molecular profiles, with implications for interpreting putative allele-specific signaling dependencies and therapeutic vulnerabilities.

DOI: https://doi.org/10.64898/2026.03.10.710185
Dev Cell. 2026 Apr 08. pii: S1534-5807(26)00086-9. [Epub ahead of print]61(4): 709-710

Lysosomal rupture: An emerging switch for collective ferroptosis.

Wenxin Zhang, Junren Dai, Ying Hu.

Ferroptosis can propagate collectively between cells. In this issue of Developmental Cell, Das et al.1 report that glutathione (GSH) depletion converts glutathione peroxidase 4 (GPX4)-inhibition-induced ferroptosis from a single-cell to a collective fate, and confirms the central role of lysosomal rupture in this process.

DOI: https://doi.org/10.1016/j.devcel.2026.03.002
Cancer Discov. 2026 Apr 03. OF1

Pancreatic Cancer Interception with RAS Inhibition Improves Survival.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2026-036
Nat Metab. 2026 Apr 07.

Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.

Jennifer A Brain, Anna-Lena B G Vigil, Kristian Davidsen, Ayaha Itokawa, Abby C Jurasin, Hannah J Kerbyson, Maximilian Kobiesa, Madeleine L Hart, Sang Jun Yoon, Peter Bellotti, Juan Pablo Maianti, Gina M DeNicola, Lucas B Sullivan.

Cancer cells with constitutive NRF2 activation take up excess cystine beyond the cysteine demands of conventional pathways, implying unknown metabolic fates. Here, we develop an unbiased approach for the identification of cysteine metabolic fates and find that both known and previously uncharacterized cysteine-derived metabolites accumulate in NRF2-activated cancer cells. We identify many of these unknown metabolites as conjugates formed between cysteine and endogenous sugar metabolites, which can also be generated in vitro. We confirm the presence of these cysteine-derived conjugates in murine lung cancer models and primary human lung cancer samples, and their enrichment in NRF2-activated tumours in each context. Mechanistically, NRF2 promotes cystine uptake by driving SLC7A11 expression, which increases intracellular cysteine levels to promote these cysteine fates in a panel of cancer cell lines. Finally, we show that NRF2 activation creates a sensitivity to high environmental cystine, which impairs cell proliferation through excess free cysteine, and can be mitigated by sequestration into cysteine-derived conjugates. Overall, these findings reveal a cancer-associated metabolic vulnerability to excess cysteine stress, and reveal unrecognized routes of cysteine metabolism.

DOI: https://doi.org/10.1038/s42255-026-01499-8
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2520717123

Amoeboid-mesenchymal transition and the proteolytic control of cancer invasion plasticity.

Adam W Olson, Jonathan Li, Xiao-Yan Li, Lana King, Long Jiang, Kalins Banerjee, Atticus J McCoy, Mahnoor N Gondal, Arul M Chinnaiyan, Dorraya El-Ashry, Evan T Keller, Andrew J Putnam, Stephen J Weiss.

  Invasion plasticity allows malignant cells to toggle between collective, mesenchymal, and amoeboid phenotypes while traversing extracellular matrix (ECM) barriers. Current dogma holds that collective and mesenchymal invasion programs trigger the mobilization of proteinases that digest structural barriers dominated by type I collagen, while amoeboid activity allows cancer cells to marshal mechanical forces to traverse tissues independently of ECM proteolysis. Here, we use cancer spheroid-3-dimensional matrix models, single-cell RNA sequencing, and human tissue explants to identify the mechanisms controlling mesenchymal versus amoeboid invasion. Unexpectedly, collective/mesenchymal- and amoeboid-type invasion programs-though distinct-are each characterized by active tunneling through ECM barriers, with expression of matrix-degradative metalloproteinases. CRISPR/Cas9-mediated targeting of a single membrane-anchored collagenase, MMP14/MT1-MMP, ablates tissue-invasive activity while coregulating cancer cell transcriptional programs. Though changes in matrix architecture, nuclear rigidity, and metabolic stress as well as the presence of cancer-associated fibroblasts are proposed to support amoeboid activity, none of these changes restore invasive activity of MMP14-targeted cancer cells. While a requirement for MMP14 is bypassed in low-density collagen hydrogels, invasion by the proteinase-deleted cells is associated with nuclear envelope and DNA damage, highlighting a proteolytic requirement for maintaining nuclear integrity. Nevertheless, when cancer cells confront explants of live human breast tissue, MMP14 is again required to support invasive activity. Corroborating these results, spatial transcriptomic and immunohistological analyses of human breast cancers identified MMP14 expression in tissue-infiltrating carcinoma cells that were further juxtaposed with proteolyzed type I collagen fragments, underlining the pathophysiologic importance of this proteinase in directing invasive activity in vivo.

Keywords:  amoeboid; cancer; invasion; proteinase

DOI:  https://doi.org/10.1073/pnas.2520717123
J Cell Sci. 2026 Apr 01. pii: jcs264503. [Epub ahead of print]139(7):

Membrane integrity control - from lipids to proteins and back to lipids.

Baicong Mu, Dan Zhang.

  Membrane integrity is vital for cell survival and function. Despite constant mechanical and chemical challenges, cellular membranes exhibit remarkable resilience through highly coordinated protective and repair mechanisms. Here, we outline a mechanistic framework in which biological membranes function as dynamic mechano-chemical integrators, linking lipid physicochemical properties with protein-mediated stress responses and Ca2+ signaling to maintain membrane integrity. We further discuss how intrinsic bilayer features give rise to both distinct and shared strategies that safeguard membrane homeostasis. We also highlight the emerging roles of lipid transporters and biomolecular condensates in membrane stress surveillance and repair. Collectively, we propose that lipid-protein-lipid feedback loops, in which membrane perturbations activate protein effectors that remodel bilayer composition or organization, form robust circuits enabling rapid sensing, signal amplification, and membrane adaptation and repair, thereby preserving membrane integrity under fluctuating stress conditions.

Keywords:  Biomolecular condensates; Calcium signaling; Lipid transfer protein; Membrane biophysics; Membrane contact sites; Membrane integrity; Membrane repair; Non-vesicular lipid transfer

DOI:  https://doi.org/10.1242/jcs.264503
Cell. 2026 Apr 03. pii: S0092-8674(26)00272-2. [Epub ahead of print]

Senescence in cancer: Hallmarks, paradoxes, and therapeutic promise.

Clemens Hinterleitner, Hailey V Goldberg, Domhnall McHugh, Valentin J A Barthet, Aveline Filliol, Scott W Lowe.

Cellular senescence is a conserved stress-responsive program defined by durable proliferative arrest and extensive remodeling of chromatin, metabolism, intercellular signaling, and immune interactions. Initially described as a barrier to unlimited cell division, senescence is now recognized as a pleiotropic and heterogeneous biological process with roles in development, tissue repair, immune surveillance, tumor suppression, aging, fibrosis, and cancer progression. Despite its broad relevance, senescence remains challenging to define operationally, as its molecular features, functional outputs, and physiological consequences vary across cell types, tissues, and stimuli. This review summarizes core hallmarks of senescence while synthesizing how these features are differentially engaged, diversified, and repurposed across biological contexts. Focusing on cancer, we discuss how senescence influences tumor initiation, evolution, and therapeutic response through both cell-intrinsic and microenvironmental mechanisms. We further evaluate emerging strategies to therapeutically modulate senescence, highlighting both opportunities and unresolved challenges for precision intervention.

DOI: https://doi.org/10.1016/j.cell.2026.03.005
Biochim Biophys Acta Biomembr. 2026 Apr 08. pii: S0005-2736(26)00034-9. [Epub ahead of print] 184531

Ten questions on membrane biophysics.

Georg Pabst, Carolyn Vargas, Sandro Keller.

  Biological membranes are among the most complex and functionally versatile structures in living cells. In this perspective, dedicated to the memory of Joachim Seelig, we explore ten questions that, in our view, define the current frontiers of membrane biophysics. We begin by asking why cells maintain such extraordinary lipid diversity when, as recent work on minimal cells demonstrates, life can survive with just two lipid species. We examine membrane asymmetry and its functional consequences, the nature of protein-lipid interactions, and how the membrane itself can act as an allosteric modulator of protein function through physical mechanisms such as the lateral pressure profile. We consider the controversy surrounding lipid rafts, the consequences of membrane crowding, and what we sacrifice when studying membranes and membrane proteins using mimetic systems. We explore membranes as non-equilibrium systems maintained by continuous free-energy dissipation, the challenges of targeting membranes pharmacologically, and how membranes evolved and develop. Throughout, we emphasize that membranes are not passive barriers but active participants in cellular function, shaped by billions of years of evolution and endowed with a compositional complexity we are only beginning to understand.

Keywords:  Lateral pressure profile; Lipid diversity; Lipid rafts; Membrane asymmetry; Membrane biophysics; Membrane mimetics; Non-equilibrium biophysics; Protein–lipid interactions

DOI:  https://doi.org/10.1016/j.bbamem.2026.184531
bioRxiv. 2026 Apr 02. pii: 2026.04.01.715929. [Epub ahead of print]

Coupling between sterol and sphingolipid structure in ordered membrane domains.

Israel Juarez-Contreras, Hyesoo Kim, Itay Budin.

A hallmark of eukaryotic membranes is the pairing of lineage-specific sterols with characteristic sphingolipid species. Mammalian cell membranes are enriched in both cholesterol and long-chain sphingolipids like sphingomyelin, whereas fungi synthesize ergosterol and very long-chain sphingolipids with sugar-containing head groups. It has been proposed that these two lipid classes co-evolved to support membrane structure and organization. Here we investigated how sterol structure and sphingolipid chain length together control membrane order and phase behavior. In the yeast Saccharomyces cerevisiae , loss of very long-chain C26 sphingolipids disrupted formation of liquid-ordered ( L o ) domains in the vacuole membrane. Similarly, substitution of ergosterol synthesis for that of cholesterol also prevented vacuole L o domains. To determine a possible physical basis of these effects, we investigated synthetic membranes of defined composition containing either ergosterol or cholesterol and sphingomyelin with different chain lengths. In membranes containing egg sphingomyelin with C16 chains, ergosterol only sparsely supported L o domains, in contrast to cholesterol. Membranes containing sphingomyelin with C26 chains displayed a different pattern. Cholesterol mixtures were largely homogeneous across most compositions, with only a limited region that supported fluid domains. Ergosterol mixtures exhibited a distinct compositional window that supported fluid domains positioned between regimes of uniform membranes and gel phases. This window corresponded to stoichiometric changes in the vacuole as it phase-separates during nutritional restriction. Measurements of membrane order showed that cholesterol strongly increased membrane packing compared to ergosterol in membranes containing egg sphingomyelin, whereas this difference was lost in membranes containing C26 sphingomyelin. The results suggest that sphingolipid chain length can tune sterol interactions needed for membrane organization.
Significance: Membrane phase separation into coexisting ordered and disordered fluid domains has largely been investigated using characteristic mammalian lipid components, cholesterol and long-chain saturated lipids like sphingomyelin. Under nutrient limitation, vacuole membranes in yeast organize into micron-scale domains that are important for their physiology. Compared to mammals, yeast synthesize an alternative sterol, ergosterol, and sphingolipids with very long-chains. We show that vacuole membrane domains are sensitive to both these features, which also show preferential interactions in liposomes that support membrane ordering and phase properties. In lipid mixtures containing very long-chain sphingomyelins, stoichiometric regimes that support phase separation of fluid domains are similar to those of the vacuole lipidome under nutrient limitation. This finding supports a model in which sterols and sphingolipids co-evolved to support membrane structure.

DOI: https://doi.org/10.64898/2026.04.01.715929
Nat Rev Mol Cell Biol. 2026 Apr 09.

Phase separation across membranes and condensates in cell organization and function.

Agustín Mangiarotti, Rumiana Dimova.

Phase separation is a fundamental principle of cellular organization that typically leads to two coexisting phases: a dense one, where intermolecular interactions are stronger and molecules are more tightly packed, and a dilute, less packed phase, with weaker interactions and lower molecular concentration. This process drives the formation of both lateral membrane domains (rafts) and liquid-like protein and nucleic acid condensates. This Review explores the dynamic interplay between biomolecular condensates and membrane lipid domains and how phase separation occurs in the three-dimensional (bulk) cellular interior and at two-dimensional membrane interfaces. We examine how membranes act as platforms influencing condensate formation and function and, conversely, how condensates modulate membrane properties and organization. By highlighting diverse examples from cell signalling, tight-junction assembly and stress responses, we emphasize how these coupled interactions are crucial for cellular organization, function and fitness.

DOI: https://doi.org/10.1038/s41580-026-00961-5
Front Cell Dev Biol. 2026 ;14 1756238

A feedback loop between cell proliferation and ROS regulates ferroptosis sensitivity.

Eric Seidel, E Yaren Itak, Fabienne Müller, F Isil Yapici, Johannes Brägelmann, Johannes Berg, Silvia von Karstedt.

   Background: Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation and membrane rupture. While cellular populations reaching confluence are known to have limited sensitivity to ferroptosis, an understanding of the interplay between growth dynamics, reactive oxygen species (ROS) levels, metabolism and ferroptosis is currently lacking. This study aimed to establish a regulatory framework for the systemic interplay of these biological processes.
Results: Here we use live-cell imaging coupled to ROS tracing to reveal a feedback loop between population growth and ferroptotic cell death. Starting out from the observation that the cellular proliferation rate declines with increased cellular density, we find that ROS levels also decline with increasing cellular density. In turn, low ROS levels make cells insensitive to ferroptosis, which enables population growth. Conversely, keeping cell numbers and drug concentration/cell constant while restricting growth space led to reduced proliferation, reduced ROS and decreased ferroptotic cell death. We find that this feedback between population growth and ferroptotic cell death leads to two steady states: (i) a ferroptosis-insensitive state characterized by slow growth, low levels of ROS and low rates of cell death and (ii) a ferroptosis-sensitive state characterized by rapid growth, ROS accumulation, and high rates of ferroptosis. A mathematical model of the feedback mechanism predicts the long-term fate of populations as well as their ferroptosis sensitivity when external conditions impacting cell proliferation rates, ROS, or both are changed. We tested the proposed feedback mechanism experimentally by interfering with lipid hydroperoxide clearance and by increasing cellular and lipid ROS production through a galactose-promoted OXPHOS switch.
Conclusion: We find a feedback loop between population growth and ferroptotic cell death that dictates cellular fate (growth or cell death via ferroptosis) and is mechanistically determined by the levels of metabolic ROS. These results provide a unifying framework that dynamically links population growth and metabolic ROS regulation with ferroptosis sensitivity.

Keywords:  ROS; feeedback loop; ferroptosis; lipid ROS; modelling

DOI:  https://doi.org/10.3389/fcell.2026.1756238
Trends Immunol. 2026 Apr 09. pii: S1471-4906(26)00069-4. [Epub ahead of print]

Immunoferroptosis: ferroptosis meets tumor immunity and immunotherapy.

Xin Chen.

  Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has attracted considerable attention in tumor biology and cancer therapy. Beyond its intrinsic role in tumor suppression, ferroptosis greatly influences the tumor immune microenvironment. Ferroptotic tumor cells release damage-associated molecular patterns, oxidized lipid mediators, and nucleic acids, which can either activate or suppress antitumor immunity. Conversely, immune cells modulate tumor cell sensitivity to ferroptosis through the secretion of cytokines and metabolites. In this review, we summarize the current understanding of the interplay between ferroptosis and tumor immunity. Targeting ferroptosis may offer broad opportunities to enhance tumor immunotherapy.

Keywords:  ferroptosis; immune evasion; immunoferroptosis; immunotherapy; tumor immunity

DOI:  https://doi.org/10.1016/j.it.2026.03.008
bioRxiv. 2026 Mar 12. pii: 2026.03.10.710937. [Epub ahead of print]

Targeting Distinct Cell Cycle Nodes Overcomes KRAS/RAS Inhibitor Resistance.

Vishnu Kumarasamy, Jianxin Wang, Edwin Yau, Ethan V Abel, Agnieszka K Witkiewicz, Erik S Knudsen.

Activating mutations in KRAS drive pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). Although mutant-selective KRAS inhibitors and pan-RAS inhibitors provide clinical benefits, the development of resistance limits durable response. Transcriptomic and proteomic analyses reveal that, despite effective suppression of mutant KRAS signaling, resistant cells sustain cell cycle progression. Distinct orthogonal mitogenic pathways are engaged in a context-dependent manner to bypass KRAS inhibition. While these pathways can be broadly inhibited using the pan-RAS-ON inhibitor RMC-6236, cells remained capable of developing acquired resistance where cell proliferation is uncoupled from RAS signaling. Combinatorial drug screens and genome-wide CRISPR-Cas9 screens reveal that perturbing cell cycle nodes via targeting cyclin dependent kinases CDK4/6 and CDK2 could restore sensitivity to KRAS/RAS inhibitors. Co-targeting CDK4/6 induces G1 arrest and suppresses E2F-regulated proteins across all resistant models. In contrast, co-targeting CDK2 exerts a broader effect by impairing DNA replication, inducing G2 arrest, preventing mitotic entry, and yielding a more durable cytostatic response that delays cellular outgrowth after drug withdrawal. Finally, concurrent inhibition of KRAS with either CDK4/6 or CDK2 yields durable tumor control in vivo in xenografts derived from acquired resistant models. In conclusion, our findings identify sustained cell cycle activity as a defining feature of resistance to KRAS-directed therapies and establish cell cycle co-targeting as an effective strategy to overcome KRAS/RAS inhibitor resistance.

DOI: https://doi.org/10.64898/2026.03.10.710937
Nat Commun. 2026 Apr 10.

Translation in proximity to forming autophagosomes during sustained autophagy.

Yunping Xue, Kaela O'Connor, Karsten Nalbach, Alexandre Savard, Karyn E King, Ryan C Russell, Christian Behrends, Derrick Gibbings.

Autophagy is an evolutionarily conserved catabolic process. In a process requiring a cascade of over 35 autophagy-related genes (Atg), a cupped phagophore membrane expands to surround cytoplasmic material, and seals itself to form an autophagosome, which finally fuses with lysosomes. Large numbers of autophagosomes form during stress responses, while simultaneously cells drastically reduce translation to conserve energy. Here, using proximity-labeling and Fluorescence in situ Hybridization we demonstrate that multiple mRNAs encoding proteins required for autophagy preferentially localize in proximity to forming autophagosomes. Polysome fractionation and proteomics of nascent proteins in proximity to forming autophagosomes provides evidence for the local translation of these mRNAs. Translation and the ribosome-binding protein RACK1 were required for the localization of these mRNAs to forming autophagosomes. Inhibition of translation or knockdown of RACK1 caused depletion of several proteins required for autophagy and a reduction in the number of autophagosomes. Local translation may enable a rapid, energy-efficient supply of proteins for autophagy to enable cells to massively induce autophagy while conserving energy during cell stress.

DOI: https://doi.org/10.1038/s41467-026-71551-4
Autophagy. 2026 Apr 11. 1-17

NCOA4-mediated ferritinophagy: emerging role and novel therapeutic target in precision oncology.

Dengwang Chen, Xinyue Jiang, Tao Duan, Ying Tian, Jidong Zhang, Xin Wang, Jun Tan.

  Iron is vital for life but can be toxic in excess by forming reactive oxygen species. Ferroptosis, a type of regulated cell death, relies on iron-dependent lipid peroxidation and requires a labile iron pool (LIP) in cells. Ferritin stores iron safely, and its degradation increases the LIP. Ferritinophagy, the autophagic breakdown of ferritin, is crucial for releasing stored iron to trigger ferroptosis. This review examines ferritinophagy's molecular mechanisms, highlighting NCOA4 (nuclear receptor coactivator 4) as the main receptor targeting ferritin for lysosomal degradation. It also discusses the regulatory network controlling NCOA4, including transcriptional factors like TP53/p53 and MYC/c-Myc, RNA-binding proteins, and post-translational modifications such as ubiquitination. We explore ferritinophagy-induced ferroptosis as a promising anti-cancer approach. Research shows that various natural compounds, repurposed drugs, and new metal complexes can induce tumor cell death by activating the NCOA4-ferritinophagy pathway, which is crucial for overcoming therapeutic resistance in many cancers. Understanding this pathway highlights the relationship between iron metabolism, macroautophagy/autophagy, and cell death, offering a foundation for new treatments for cancer and iron-related diseases.Abbreviation: FTH1: ferritin heavy chain 1; GPX4: glutathione peroxidase 4; GSH: glutathione; HIF: hypoxia-inducible factor; LIP: labile iron pool; MAPK/JNK: mitogen-activated protein kinase; NCOA4: nuclear receptor coactivator 4; PUFAs: polyunsaturated fatty acids; SLC7A11: solute carrier family 7 member 11; TFRC: transferrin receptor; TFEB: transcription factor EB.

Keywords:  Cancer therapy; NCOA4; ferritinophagy; ferroptosis; iron metabolism; therapeutic resistance

DOI:  https://doi.org/10.1080/15548627.2026.2656779
Cancer Discov. 2026 Apr 01. OF1

Epithelial-Fibroblast Crosstalk Supports Early Tumorigenesis.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2026-035
Commun Biol. 2026 Apr 08. pii: 519. [Epub ahead of print]9(1):

OncoRisk: a state-of-the-art web server for bridging the oncogenic databases and pan-cancer cohorts to the translational oncology.

Xiya Song, Emre Green, Xinmeng Liao, Hasan Turkez, Gozde Yesil, Bayram Yuksel, Mathias Uhlen, Cheng Zhang, Adil Mardinoglu.

Accurate interpretation of genomic variants remains a major bottleneck in precision oncology, due in part to fragmented knowledge across databases and limited integration between clinical evidence and population-scale genomic datasets. Here we present OncoRisk, a stand-alone, user-friendly web server that unifies data from over ten oncogenic databases and seven large-scale pan-cancer cohorts, enabling rapid multi-database queries and network-based exploration of genomic variants, gene-gene interactions, and therapy associations. The platform features a semi-automated reporting workflow that generates comprehensive, patient-specific clinical reports from raw tissue sequencing data and categorizes variants into actionable tiers. For translational research, OncoRisk provides modules for data-driven exploration, allowing users to validate findings by interrogating mutation frequencies and clinical associations across real-world patient data. Furthermore, an integrated suite of analytical tools enables comprehensive, cohort-level investigations of mutational landscapes, prognostic biomarkers, and oncogenic signaling pathways. By providing a unified ecosystem that bridges curated knowledge with large-scale cohort data, OncoRisk serves as an effective catalyst for both discovery research and clinical application in oncology. OncoRisk is publicly available at https://www.phenomeportal.org/oncorisk .

DOI: https://doi.org/10.1038/s42003-026-10005-5
Am J Physiol Gastrointest Liver Physiol. 2026 Apr 09.

Fibroblast-Specific GPX4 Deletion Exacerbates IBD via Lipid Peroxidation.

Yuezhong Zhang, Yinzhi Ying, Wesley Huang, Zoe A Rosenfeld, Marwa O El-Derany, Zheng Hong Lee, Cristina Castillo, Tae Gyu Oh, Joel K Greenson, Yatrik M Shah.

  Broad antioxidant strategies in inflammatory bowel disease have had limited success, likely because they indiscriminately quench both harmful and physiological reactive oxygen species (ROS). In our recent work, we demonstrated that fibroblast-specific overexpression of acyl-CoA synthetase long-chain family member 4 (ACSL4) reprogrammed lipid metabolism and sensitized adjacent epithelial cells to ferroptosis in IBD models, pointing to heterocellular lipid crosstalk as a driver of epithelial injury. Building on that insight, here we test the hypothesis that fibroblast glutathione peroxidase 4 (GPX4), a key enzyme detoxifying lipid hydroperoxides, is critical in restraining fibroblast-mediated lipid peroxidation and consequent epithelial ferroptosis during colitis. We generated tamoxifen-inducible fibroblast-specific GPX4 knockout mice and subjected them to acute DSS colitis. Fibroblast-specific GPX4 deletion did not alter basal colon morphology but significantly aggravated DSS-induced injury. Increased histological scores, greater weight loss, and colon shortening versus littermate control mice. In vitro, GPX4-deficient fibroblasts exhibited elevated lipid peroxidation in response to ferroptosis inducers, reversible by liproxstatin-1. Critically, liproxstatin-1 treatment rescued colitis severity in fibroblast-GPX4-deficient animals, restoring colon length, weight loss, and histologic injury. Together, these findings identify fibroblast GPX4 as a gatekeeper that limits stromal lipid peroxidation and suppresses epithelial ferroptosis under inflammatory stress. Targeting fibroblast-mediated lipid peroxidation may offer a refined therapeutic axis in IBD.

Keywords:  GPX4; inflammatory bowel disease; lipid peroxidation

DOI:  https://doi.org/10.1152/ajpgi.00387.2025
Cell Mol Immunol. 2026 Apr 07.

Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.

Yun-Wei Du, Ze-Rong Cai, Xiao-Tong Duan, Xin-Yu Li, Tong Yue, Tian Tian, Jian-Jun Li, Huai-Qiang Ju.

  Given the fundamental biological importance of lipids not only as structural components and energy substrates but also as potent bioactive molecules that govern immune and oncogenic signaling, lipid metabolism reprogramming has emerged as a central driver of tumor progression. Rather than merely fueling tumor growth, this extensive metabolic rewiring profoundly reshapes the tumor microenvironment (TME), establishing complex metabolic crosstalk that actively drives immune evasion. This review examines the current understanding of lipid metabolism reprogramming across different cellular compartments within the TME and its far-reaching implications for cancer immunotherapy. We first delineate how altered lipid metabolism directly fuels tumor cell proliferation, survival, and metastatic potential. We then examine the distinct lipid metabolic patterns in different immune cells, detailing how this reprogramming drives dysfunction in antitumor subsets such as CD8+ T cells and natural killer cells and how it promotes immunosuppressive populations such as tumor-associated macrophages and myeloid-derived suppressor cells. In addition to these immune alterations, we address the metabolic rewiring of stromal cells, particularly cancer-associated fibroblasts. Furthermore, by exploring intricate intercellular crosstalk, we highlight how tumor lipid metabolism promotes immune escape and how lipids from reprogrammed immune and stromal cells, in turn, support tumor growth, thereby reinforcing an immunosuppressive niche. Finally, we highlight emerging therapeutic strategies targeting these pathways and discuss how leveraging multiomics advances can translate lipid insights into cancer immunotherapy.

Keywords:  Lipid metabolism reprogramming; antitumor immunity; immune evasion; tumor microenvironment

DOI:  https://doi.org/10.1038/s41423-026-01411-0
bioRxiv. 2026 Mar 10. pii: 2026.03.06.709938. [Epub ahead of print]

AQuA2-Cloud: a web platform for fluorescence bioimaging activity analysis.

Mark Bright, Xuelong Mi, Daniela Duarte, Erin Carey, Boyu Lyu, Yihzi Wang, Axel Nimmerjahn, Guoqiang Yu.

Background: Advanced biological imaging analysis platforms such as Activity Quantification and Analysis (AQuA2) enable accurate spatiotemporal activity analysis across diverse cell populations within many species. These tools are increasingly important for investigating cellular signaling dynamics and behavior. However, despite advances in the accuracy and species capability of AQuA2, it remains computationally demanding for analysis of long time-series datasets and requires all users to maintain a MATLAB license, which may limit accessibility and large-scale deployment.
Results: To address these limitations, we have designed and made available AQuA2-Cloud , a portable software stack and web platform developed as an improvement and further evolution of AQuA2. This container-deployable system permits multi-user cloud-based high accuracy activity quantification with intuitive workflows, export of analysis data and project files, and comparable processing times. The platform offers integrated features such as in-browser analysis control interfaces, asynchronous program state control, multiple users and user management, support for unreliable connections, file uploading and downloading via web browsers and File Transfer Protocol, and centralized organization of analysis output.
Conclusion: AQuA2-Cloud constitutes a cloud-native solution for laboratories or research groups seeking to centralize analysis of spatiotemporal biological imaging datasets while reducing software installation and licensing barriers for end users. The platform enables researchers with minimal technical expertise to perform advanced bioimaging analysis through standard web browsers while maintaining the analytical capabilities of AQuA2. AQuA2-Cloud source code, deployment procedures, and documentation are freely available at ( https://github.com/yu-lab-vt/AQuA2-Cloud ).

DOI: https://doi.org/10.64898/2026.03.06.709938
Cell Metab. 2026 Apr 07. pii: S1550-4131(26)00054-9. [Epub ahead of print]38(4): 635-637

Vitamin C slows primate aging by targeting iron-driven lipid peroxidation.

Pei-Long Yu, Cheng-Ran Xu.

Aging has long been associated with oxidative stress, yet its underlying metabolic drivers remain unclear. Liu et al. identify a conserved, iron-driven lipid peroxidation of primate aging mediated by ACSL4 and demonstrate that vitamin C directly suppresses this process, offering a translatable strategy to mitigate age-associated functional decline.

DOI: https://doi.org/10.1016/j.cmet.2026.02.011
bioRxiv. 2026 Apr 05. pii: 2026.04.02.713930. [Epub ahead of print]

NucleoNet and DropNet: Generalist deep learning models for instance segmentation of nuclei and lipid droplets from electron microscopy images.

Abhishek Bhardwaj, Chris W Dell, Melissa R Mikolaj, Helen Spiers, Adam Harned, Balamurugan Kuppusamy, Peng Liu, Donglai Wei, Esta Sterneck, Kedar Narayan.

Automating cellular organelle segmentation is key to increasing the throughput in electron microscopy (EM) and volume EM (vEM) workflows. Deep learning (DL) has accelerated this process, but model development has predominately centered on mitochondria, partly because of a scarcity of suitable training datasets for other features. Here, we crowdsourced the manual step of labeling nuclei and lipid droplets (LDs) from complex cellular EM images and trained Panoptic DeepLab (PDL) models on these large, heterogenous annotated datasets as well as on publicly available vEM datasets. NucleoNet and DropNet , the resulting instance segmentation models for nuclei and LDs, respectively, yield high-quality results on varied benchmarks. We applied these models to quantify differences between 2D and 3D in vitro cancer models versus in vivo tumors, highlighting a path toward robust quantitation in EM. NucleoNet and DropNet are publicly available on our napari plugin, empanada v1.2 , for easy point-and-click segmentation of 2D and 3D cellular EM images.

DOI: https://doi.org/10.64898/2026.04.02.713930
Oncogene. 2026 Apr 07.

Hypoxia-induced XBP1s-MYDGF axis suppresses ferroptosis through UBQLN1-mediated stabilization of LCN2 in gastric cancer.

Qi Zhou, Hongyan Qi, Yonghui Zou, Zhenqi Yue, Jinheng Gan, Hesong Xu, Luojun Fan, Hua Wan, Lin Xin.

Solid tumors such as gastric cancers exploit hypoxia-induced adaptive mechanisms to evade cell death. Here, we identify a hypoxia-triggered signaling axis in which the spliced form of XBP1s transcriptionally activates MYDGF. We demonstrate that MYDGF competitively binds the ubiquitin adaptor protein UBQLN1 at the STI1-4 domain, thereby blocking UBQLN1-mediated recognition and endoplasmic reticulum-associated degradation (ERAD) of LCN2. Stabilized LCN2 sequesters redox-active iron and inhibits iron-dependent lipid peroxidation, thereby suppressing ferroptosis. Hypoxia promotes the splicing of XBP1s, which directly binds to the MYDGF promoter, increasing its expression. Genetic disruption of this axis sensitizes gastric cancer cells to ferroptosis inducers both in vitro and in vivo. These findings reveal a previously unrecognized mechanism of hypoxia-induced ferroptosis resistance and suggest that the XBP1-MYDGF-UBQLN1-LCN2 pathway is a therapeutic target for hypoxic tumors.

DOI: https://doi.org/10.1038/s41388-026-03760-6
Mol Cell. 2026 Apr 07. pii: S1097-2765(26)00189-9. [Epub ahead of print]

Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF.

Christoph Nössing, Olga Troitskaya, Jaclyn S Long, Andrew Craxton, Martina Brucoli, Eve Anderson, Sergio Lilla, David G McEwan, Annabel R Minton, Valentin J A Barthet, Jim O'Prey, Gemma Thomson, Colin Nixon, Sara Zanivan, Douglas Strathdee, Marion MacFarlane, Kevin M Ryan.

  Inflammation can affect many diseases. We report here that inflammatory cytokines invoke caspase-8-mediated cleavage of the autophagy adaptor p62/SQSTM1 at aspartic acid 329 in human cells, producing a previously described truncated form, which we term tr-p62. We show that TNF-driven cell death is tr-p62 dependent and that autophagy inhibition promotes death via tr-p62 accumulation. Mechanistically, p62 cleavage is receptor-interacting serine/threonine-protein kinase 1 (RIPK1) dependent, and tr-p62 stabilizes caspase-8 activating complex-IIb. tr-p62-driven cell death downstream of TNF is also RIPK1 and caspase dependent, promoting feedforward caspase-8 activation. p62 cleavage does not, however, affect necroptosis. Surprisingly, this caspase-8 cleavage site in p62 is absent in mice, and introduction of cleavable forms of p62 into mouse cells causes sensitization to TNF-induced death. Moreover, mice with CRISPR-Cas9-generated cleavable p62 exhibit TNF hypersensitivity and intestinal inflammation in vivo. These findings provide significant insights into TNF-induced cell death and introduce a mouse model that may provide better clarity for human-related studies of inflammatory disease.

Keywords:  TNF; autophagy; caspase; cell death; mice; p62

DOI:  https://doi.org/10.1016/j.molcel.2026.03.013
bioRxiv. 2026 Mar 10. pii: 2026.03.09.710628. [Epub ahead of print]

Epstein-Barr Virus Latent Membrane Protein 1 Suppresses Ferroptosis via Pentose Phosphate Pathway and Glutathione Metabolism.

Eric M Burton, Bidisha Mitra, Rui Guo, John M Asara, Benjamin E Gewurz.

Epstein-Barr virus (EBV) is associated with 200,000 cancers per year, including Burkitt lymphoma and post-transplant lymphomas. We previously reported that EBV latency oncogene programs dynamically remodel infected B cell metabolism and sensitivity to induction of ferroptosis, a programmed cell death pathway driven by lipid reactive oxygen species. However, much has remained unknown about how EBV remodels key redox defense pathways in support of infected B cell proliferation. Here, we identify EBV latent membrane protein 1 (LMP1), a key viral oncogene necessary for B cell immortalization and which mimics aspects of CD40 signaling, drives resistance to ferroptosis induction by erastin, a small molecule that blocks cystine uptake. LMP1 expression was sufficient to protect Burkitt cells from erastin ferroptosis induction. Mechanistically, signaling from the LMP1 TES2/CTAR2 region drove this phenotype, which was not shared by CD40 signaling, revealing that LMP1 evolved independent redox defense roles. Metabolomic analysis highlighted key LMP1 and TES2 signaling roles in support of antioxidant cysteine and glutathione levels. TES2 signaling supported cystine uptake, glutathione and NADPH pools in newly infected peripheral blood B cells. We identified PFKFB4, a host enzyme that shunts glucose into the pentose phosphate pathway to support NADPH production, as a major TES2 metabolic target. PFKFB4 knockdown increased EBV-transformed lymphoblastoid cell line lipid ROS levels, decreased glutathione and strongly sensitized them to ferroptosis induction by erastin treatment. PFKFB4 was also necessary for LMP1-mediated Burkitt B cell ferroptosis resistance. Collectively, these results identify PFKFB4 as a key host cell EBV metabolism remodeling target critical for infected B cell redox defense.

DOI: https://doi.org/10.64898/2026.03.09.710628