bims-ginsta 2026-06-21 papers

bims-ginsta

Biomed News

on Genome instability

Issue of 2026–06–21
thirty papers selected by
Jinrong Hu, National University of Singapore

Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
Pioneer-factor activity requires stable chromatin occupancy mediated by both sequence-specific binding and disordered protein domains.
Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.
L1CAM signaling through planar cell polarity drives SOX2 expression and lung adenocarcinoma metastasis.
Mitotic Cdc42 waves encode PI(3,4)P2 signaling and Golgi morphological state to control spindle scaling.
Boundary constraints can determine pattern emergence.
ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.
Aging disrupts spatiotemporal coordination in the cycling murine ovary.
Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.
Structure of the pre-initiation complex explains CMGE biogenesis.
Adhesion-driven rigidity transition decoupled from density-driven jamming triggers epithelial organization in embryonic tissues.
Structures of protein folding intermediates on the ribosome.
Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging.
Epithelial cell extrusion underlies starvation-induced cell loss in a sea anemone.
Conformational cycling of the Wntless transporter drives trafficking and secretion of Wnt morphogens.
Confined migration induces non-lethal DNA damage in developing neurons.
Vacuolar H+-ATPase Preserves Cardiolipin Homeostasis Through the Lysosomal-Mitochondrial Axis to Restrain Cardiac Aging.
Epithelial cells fire voltage spikes.
NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.
Alternative 3' UTRs and RNA-binding proteins Ewsr1b, HuR, and Syncrip organize sequential waves of translation to drive embryonic development.
Diminished transcriptional activity and splicing changes drive gene length-biased rewiring in the aging transcriptome.
Live imaging and multimodal profiling reveal transdifferentiation of a cochlear supporting cell subpopulation upon Notch inhibition.
The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.
Programmed synthesis of mesoporous protein crystals in cellular reactors.
LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance.
Mechanisms and interventions of epigenetic aging.
Meiotic pairing through barcode-like satellite DNA repeats.
Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis.
FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.
Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.

Nat Cell Biol. 2026 Jun 15.

Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.

Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.

Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.

DOI: https://doi.org/10.1038/s41556-026-01991-z
Sci Adv. 2026 Jun 19. 12(25): eaef2244

Pioneer-factor activity requires stable chromatin occupancy mediated by both sequence-specific binding and disordered protein domains.

Meghan M Freund, F Javier deHaro-Arbona, Sarah Baloul, Ali Torhorst, Charalambos Roussos, Abby J Ruffridge, Andrew Q Rashoff, Ryen Hazzard, Peter W Lewis, Sarah J Bray, Melissa M Harrison.

Pioneer transcription factors overcome the restrictive barrier imposed by chromatin to drive cell-fate specification, yet how their domains collectively support this activity remains unclear. Here, we use the deeply conserved pioneer factor Grainy head to define the protein-intrinsic features that govern pioneering activity. By integrating biochemistry, genomics, and quantitative live-cell imaging, we determined that both the conserved DNA-binding domain and the extended, intrinsically disordered N terminus are required for the stable chromatin occupancy that supports access to closed chromatin and the induction of chromatin accessibility. The disordered N terminus supports pioneer activity through interactions that do not rely on strict amino acid sequence but instead on overall composition. While our results show that pioneering activity depends on the combinatorial contributions of structured and disordered domains, mitotic retention depends solely on sequence-specific DNA binding. These results support stable chromatin occupancy mediated by multiple protein domains as necessary for pioneering function and that this is separable from the mechanisms required for mitotic retention.

DOI: https://doi.org/10.1126/sciadv.aef2244
Nat Cell Biol. 2026 Jun 19.

Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.

Steven T Nguyen, Richard L Watson, Fangyuan Gao, Melissa Campos, Sunhee Jung, Laurence J Seabrook, Maxwell C Kim, Eric A Hanse, Ying Yang, Mei Kong, Jonathan E Zuckerman, Renata C Pereira, Isidro B Salusky, Sergio D Catz, Cholsoon Jang, Dorota Skowronska-Krawczyk, Lauren V Albrecht.

Lysosomes are integral organelles that communicate cellular status to an entire tissue through mechanisms that are poorly defined. Here we developed an unbiased platform, integrating human plasma metabolomes and single-lysosome metabolomics, and show the byproducts of proteolysis are an unexpected class of signalling molecules. We show that dimethylarginine is a lysosomal-derived metabolite and a predictor of patient morbidity. Genetic depletion of a lysosomal exporter, cystinosin, accumulated dimethylarginine in lysosomes. Leveraging a lysosomal storage disease with cystinosin mutations, we show that the rapid plasticity of dimethylarginine compartmentalization ensures cell and tissue homeostasis. Strikingly, lysosomal entrapment of dimethylarginine in patients and disease models corresponds with lipid accumulation, lipid droplets and lipotoxicity. Exogenously restoring asymmetric dimethylarginine buffers oxidative stress, decreasing lipid peroxidation and cell death. These data show that dimethylarginine engages an interorganellar process-with peroxisomes, lysosomes and lipid droplets-that confers a crucial adaptive response mechanism.

DOI: https://doi.org/10.1038/s41556-026-01970-4
Nat Commun. 2026 Jun 18.

L1CAM signaling through planar cell polarity drives SOX2 expression and lung adenocarcinoma metastasis.

Jin Suk Park, Yasemin Kaygusuz, Carson Kenum, Lan He, Mohamed I Gatie, Xueqian Zhuang, Roshan Sharma, Ronan Chaligné, Umesh K Bhanot, Richard P Koche, Tuomas Tammela, Anna-Katerina Hadjantonakis, Charles M Rudin, Joan Massagué.

Plasticity transitions during carcinoma progression generate fetal-like progenitor states with metastatic capacity. How these progenitors emerge and persist during tumor progression remains unclear. Here, we elucidate a process that drives the emergence of SOX2+ metastatic progenitors in lung adenocarcinomas (LUAD). LUAD cells at the tumor invasive front and distant metastases express the cell adhesion molecule L1CAM, a marker of regenerative epithelial progenitors and a mediator of cell-basement membrane and cell-cell interactions, as well as the proliferation of extravasated micrometastatic cells. We now identify a distinct and broader role of L1CAM as promoter of the SOX2+ LUAD progenitor state. We show that L1CAM at cell-cell interfaces promotes the assembly of the planar cell polarity (PCP) complex in metastatic LUAD progenitors. L1CAM-dependent PCP acting through a non-canonical WNT signaling activates c-Jun, which cooperates with the chromatin remodeling factor CHD1 to drive SOX2 expression and metastatic activity. This axis sustains the tumor-initiating and regenerative capacity of LUAD progenitor cells. By illuminating the role of L1CAM and PCP signaling in the generation of SOX2+ LUAD progenitors, our findings identify potential new targets to treat metastatic cancer.

DOI: https://doi.org/10.1038/s41467-026-74539-2
Sci Adv. 2026 Jun 19. 12(25): eaec7705

Mitotic Cdc42 waves encode PI(3,4)P2 signaling and Golgi morphological state to control spindle scaling.

Suet Yin Sarah Fung, Shengping Xiao, Yujin Bao, Morven Graham, Maohan Su, Xinran Liu, Joerg Bewersdorf, Min Wu.

Self-organizing waves are observed in numerous biological systems and may encode spatial and temporal information for cellular organization in the absence of prepatterns. In mitotic mast cells, periodic cortical waves emerge before spindle assembly with wave periods that are proportional to cell size. Here, we investigate the mechanisms that govern cortical wave scaling and examine the consequence of wave perturbation on mitotic spindle size scaling. We find that the periods of mitotic waves are regulated by the turnover of phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] on the plasma membrane, which depends on inositol polyphosphate-4-phosphatase type II (INPP4B). Genetic depletion of INPP4B increases cortical wave period and spindle length. Intriguingly, we observed mitotic wave periods that tunes continuously during mitosis, indicating the existence of a fast, posttranslational regulatory mechanism for wave scaling. We further find that the regulation of mitotic waves on the plasma membrane is controlled by the sequestering of INPP4B and PI(3,4)P2 upon mitotic Golgi fragmentation. On the basis of these findings, we propose a cell size-sensing mechanism in which cortical waves act like sonar waves, adjusting their timing and propagation based on the shuttling of signaling proteins between the cell cortex and intracellular organelles. This rapid communication scheme allows the cell to adjust spindle scaling dynamically, ensuring accurate cell division.

DOI: https://doi.org/10.1126/sciadv.aec7705
Development. 2026 Jun 15. pii: dev.205849. [Epub ahead of print]

Boundary constraints can determine pattern emergence.

Yi Ting Loo, Juliet Chen, Ryan Harrison, Tiago Rito, Sophie Theis, Guillaume Charras, James Briscoe, Timothy E Saunders.

  The robust patterning of cell fates during embryonic development requires precise coordination of signalling gradients within defined spatial constraints. Using a geometrically confined in vitro system derived from human embryonic stem cells, we demonstrate that patterning of neuromesodermal progenitors (NMPs) during axial elongation is driven by boundary-dependent mechanisms. Despite extensive work on radial fate patterning in confined 2D systems, the quantitative role of boundary conditions in shaping spatiotemporal dynamics remains unclear. Here, we show that a minimal reaction-diffusion model coupled with a simplified gene regulatory network accurately predicts spatial patterns across diverse geometries. Guided by its predictions, we identify Wnt signalling as a key component of the activator signal. Inhibition of Wnt secretion preserved initiation of patterning but disrupted subsequent morphogenesis, indicating distinct mechanisms govern pattern establishment versus maintenance. Our findings reveal how geometry encodes positional information that directs molecular patterning, providing insight into how spatial constraints and signalling dynamics guide robust tissue self-organisation during development.

Keywords:  Embryonic stem cells; Neuromesodermal progenitors; Organoid; Patterning; Phenomenological model; Reaction-diffusion

DOI:  https://doi.org/10.1242/dev.205849
Cell Stem Cell. 2026 Jun 16. pii: S1934-5909(26)00201-8. [Epub ahead of print]

ZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation.

Sanjeeb Kumar Sahu, Sebastian Memczak, Sudhir Thakurela, Jinlong Lu, Priya Gupta, Naresh Mutukula, Alex Hirano, Yingzi Zhang, Tomoaki Hishida, Masakazu Kurita, Chao Wang, Yanjiao Shao, April Williams, Max Shokhirev, Vijay K Tiwari, Concepcion Rodriguez Esteban, Pradeep Reddy, Alexander Meissner, Mo Li, Juan Carlos Izpisua Belmonte.

  Cellular senescence drives aging and disease largely through the senescence-associated secretory phenotype (SASP), yet its regulatory mechanisms remain unclear. Using a SASP reporter combined with a CRISPR-Cas9 screen targeting active regulatory elements, we identify the zinc-finger protein ZNF512B as a key suppressor of the SASP. ZNF512B loss induces DNA damage, activates cGAS-STING signaling, and triggers inflammatory transcriptional reprogramming. In contrast, ZNF512B promotes preferential DNA repair at regulatory genomic regions, limiting SASP induction. Mechanistically, ZNF512B is rapidly recruited to DNA-damage sites via distinct zinc-finger domains and facilitates NuRD complex targeting to damaged chromatin, enabling precise repair. In human neuromuscular organoids, ZNF512B deficiency induces inflammation, lineage imbalance, and cytokine secretion resembling amyotrophic lateral sclerosis (ALS)-associated pathology. In vivo, ZNF512B overexpression reduces DNA damage and inflammation following acute liver injury. Together, these findings support a mechanism of preferential DNA repair that contributes to maintaining genome integrity, suppressing SASP and inflammation.

Keywords:  CRISPR-Cas9 screening; DNA repair; SASP; ZNF512B; amyotrophic lateral sclerosis; chromatin remodeling; genome integrity; inflammation; neuromuscular organoids; senescence; senescence-associated secretory phenotype

DOI:  https://doi.org/10.1016/j.stem.2026.05.009
Nat Aging. 2026 Jun;6(6): 1244-1266

Aging disrupts spatiotemporal coordination in the cycling murine ovary.

Tammy C T Lan, Alison Kochersberger, Ruth Raichur, Sophia Szady, Hien Tran, Radiana Simeonova, Ashley Helmuth, Andrew Minagar, Maria José Orozco Fuentes, Vipin Kumar, Giovanni Marrero, Irving Barrera, Sarah Mangiameli, Alex K Shalek, Pardis C Sabeti, Fei Chen, David S Fischer, Jennifer L Garrison, Hattie Chung.

Throughout the female reproductive lifespan, the ovary undergoes hundreds of cycles of follicle development, ovulation and tissue regeneration. How aging disrupts the coordination of such precise, multicellular interactions across time and space is not well understood. Using Slide-seq, a near-cellular spatial transcriptomics method, here we profile 22 mouse ovaries across the reproductive cycle and chronological ages, capturing 610,620 spots across 69 spatial profiles. We develop a novel segmentation pipeline to examine the multicellular dynamics of 358 oocytes, 668 follicles and 236 corpora lutea to find that aging impairs the spatial and temporal coordination required for folliculogenesis even before reproductive cycles cease. These disruptions are characterized by altered immune cell dynamics, inflammatory signaling and global tissue disorganization, which impair the cyclic remodeling required for ovarian function. Our findings reveal how multicellular niches orchestrate ovarian function and demonstrate that age-related breakdown in tissue organization precedes the end of fertility.

DOI: https://doi.org/10.1038/s43587-026-01140-z
Nat Cardiovasc Res. 2026 Jun;5(6): 572-587

Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.

Johanna K Freundt, Paulina Hartmann, Christine M Loescher, Andreas Unger, Franziska Koser, Annika J Klotz, Lena Wildschütz, Lydia Wachsmuth, Susanne Hille, Michaela M Door, Anne Helfen, Richard Holtmeier, Cornelius Faber, Jonathan A Kirk, Verena Hoerr, Oliver J Müller, Wolfgang A Linke.

Titin, the largest human protein, forms the elastic sarcomeric backbone, providing passive stiffness and length-dependent activation in cardiomyocytes. Whereas titin mutations cause inherited cardiomyopathies, ischemic and chemotherapy-induced injury also provoke proteolytic cleavage of titin's elastic segment. However, the effects of acute titin stiffness loss remain unknown. Here we develop a knock-in mouse enabling in vivo cleavage of cardiac titin springs and use multimodal analysis (cardiac magnetic resonance imaging, echocardiography, microscopy, omics) to show that titin cleavage does not dilate the heart but reduces chamber size and impairs ventricular filling. Mechanical assays of isolated cardiomyocytes reveal diminished restoring forces causing a loss of elastic recoil. In vivo cleavage disrupts junctions, including integrin linkages and connexin 43 gap junctions, widens intermyocyte space without hypertrophy or hyperplasia and drives fibroblast activation, extracellular matrix remodeling and fibrosis. Compensatory mechanisms fail, leading to decompensated heart failure. These findings establish that proteolytic titin cleavage perturbs cardiac mechanical homeostasis, driving disease and matrix stiffening.

DOI: https://doi.org/10.1038/s44161-026-00829-z
Nature. 2026 Jun 17.

Structure of the pre-initiation complex explains CMGE biogenesis.

Thomas Pühringer, Berta Canal, Giacomo Palm, Agata Butryn, Emma C Couves, Oliver Willhoft, Jacob S Lewis, John F X Diffley, Alessandro Costa.

When cells enter S phase, bidirectional DNA replication is initiated through the kinase-regulated recruitment of three activators (Cdc45, GINS and Pol ε) to a duplex-DNA-loaded double hexamer of minichromosome maintenance (MCM) ATPases. Together, these proteins form two CMGE helicases that establish divergent replication forks as they become separated1. Here, to gain an understanding of CMGE biogenesis, we reconstituted the pre-initiation complex with purified yeast proteins. The cryo-electron-microscopy structure shows a set of firing factors caught in the act of assembling two symmetrical CMGEs. We show how stepwise complex formation reshapes MCM in preparation for DNA opening, and we explain how ATP promotes firing-factor ejection and CMGE maturation. We find that although Sld2 facilitates the recruitment of GINS to MCM, as expected, it also aids the efficient separation of the CMGE dimer, and is essential for the ejection of the lagging strand from MCM. These findings have direct implications for our understanding of the metazoan Sld2 orthologue, RECQL4, and point to a replication-fork establishment mechanism that is conserved across eukaryotes.

DOI: https://doi.org/10.1038/s41586-026-10657-7
Nat Phys. 2026 ;22(6): 941-953

Adhesion-driven rigidity transition decoupled from density-driven jamming triggers epithelial organization in embryonic tissues.

Laura Rustarazo-Calvo, Cristina Pallares-Cartes, Adrián Aguirre-Tamaral, Elisa Floris, Maximilian Hingerl, Camilla Autorino, Arif Ul Maula Khan, Bernat Corominas-Murtra, Nicoletta I Petridou.

  The active regulation of tissue material properties via phase transitions is central in morphogenesis. Transitions occur abruptly at critical points in different control parameters, such as cell density, shape or adhesion. Whether these parameters are interdependent, and perform redundant or distinct functions, is unknown. Here we show that depending on the co-regulation of multiple control parameters, a tissue not only tunes its deformability but also its morphogenetic trajectory. We theoretically define a phase diagram capturing the material states of zebrafish pluripotent tissues undergoing epiboly-a tissue movement occurring during gastrulation-and show that they simultaneously cross critical points in cell density, connectivity and adhesion strength. We then combine optogenetics, biophysical measurements and quantitative morphometrics to independently modulate each parameter in vivo, and identify adhesion as the main determinant of tissue rheology. Further decoupling adhesion from density and inducing adhesion-driven rigidification in unjammed pluripotent tissues is sufficient to switch their morphogenetic program and trigger epithelial organization. This switch in tissue reorganization is achieved via tricellular junction formation, followed by lumenogenesis and the initiation of apical polarity. Our work reveals that the nonlinear dynamics of emergent tissue mechanics are mechanisms of tissue organization and morphogenesis.

Keywords:  Biological physics; Biophysics; Phase transitions and critical phenomena; Soft materials; Statistical physics

DOI:  https://doi.org/10.1038/s41567-026-03276-6
Nat Struct Mol Biol. 2026 Jun;33(6): 962-972

Structures of protein folding intermediates on the ribosome.

Sammy H S Chan, Julian O Streit, Tomasz Włodarski, Alkistis N Mitropoulou, Anaïs M E Cassaignau, Ivana V Bukvin, Christopher A Waudby, Lisa D Cabrita, John Christodoulou.

The ribosome biases the conformations sampled by nascent polypeptide chains along folding pathways toward biologically active states. A hallmark of the cotranslational folding (coTF) of many proteins constitutes highly stable folding intermediates that are absent or only transiently populated off the ribosome, yet persist during translation well beyond complete emergence of the domain from the ribosome exit tunnel. Despite the importance of intermediates for folding fidelity, their structures have remained elusive and cannot be predicted by machine learning methods. Here we obtained structures of two folding intermediates of an immunoglobulin-like domain on the ribosome by developing comprehensive 19F nuclear magnetic resonance analyses using chemical shifts by rational design, paramagnetic relaxation enhancement and protein engineering, integrated with extensive molecular dynamics simulations. The resulting intermediate structures reveal native-like folded cores distinguished by nonnative termini, permitting distinct binding to a molecular chaperone and suggesting parallel folding pathways. The structures of these intermediates are conserved within the protein domain family, in contrast to their in vitro refolding mechanisms. Our detailed structural ensembles of partially folded nascent proteins on the ribosome highlight the diversity of conformations sampled during coTF, providing the ribosome with a passive means to promote efficient protein folding and maintain cellular proteostasis.

DOI: https://doi.org/10.1038/s41594-026-01814-7
Nat Aging. 2026 Jun;6(6): 1208-1226

Nuclear export of R-loop by the DDX1 and XPO1 complex promotes senescence-associated secretory phenotype and inflammaging.

Xue Hao, Bo Zhao, Qingqing Yan, Mitsutake Yano, Ayumu Matsuoka, Yuan Qi, Liping Liao, Rafal J Zielinski, Hsin-Yao Tang, Andrew V Kossenkov, M Anna Zal, Kavitha Sarma, Rugang Zhang.

Cellular senescence contributes to inflammaging in part through the senescence-associated secretory phenotype (SASP). R-loops, three-stranded nucleic acid structures, contribute to innate immune response in cancers; however, the role of R-loops in senescence and inflammaging remains largely unknown. Here we show that nuclear-derived cytoplasmic R-loops promote the SASP and inflammaging. We detect an accumulation of nuclear-derived R-loops in the cytoplasm of senescent cells with an enrichment in alpha-satellite repeats. These cytoplasmic R-loops localize into cytoplasmic chromatin fragments (CCFs) and activate the cGAS-STING innate immune pathway to drive the SASP. We identify the exportin-1 (XPO1)-DEAD-Box helicase 1 (DDX1) complex as essential for the nuclear export of R-loops and their subsequent localization into CCFs. Inhibition of XPO1 with KPT-330 suppresses nuclear R-loop export and its localization into CCFs, attenuates the SASP, mitigates age-associated inflammation and extends healthspan. These findings reveal nuclear export of R-loops as a potential target for suppressing age-associated inflammation.

DOI: https://doi.org/10.1038/s43587-026-01147-6
Nat Commun. 2026 Jun 17.

Epithelial cell extrusion underlies starvation-induced cell loss in a sea anemone.

Inés Fournon-Berodia, Noah Bruderer, Lionel Christiaen, Patrick R H Steinmetz.

Epithelia likely predate the last common animal ancestor, yet the evolutionary origin and nutritional regulation of epithelial remodelling remain poorly understood. Here, we show that extensive, starvation-induced cell loss in the sea anemone Nematostella vectensis is associated with epidermal cell extrusion. This process involves formation of a rosette-like arrangement in which an apoptotic, extruding cell is surrounded by a phospho-ERK1/2-positive ring of cells, accompanied by basal translocation of adherens junction components. Combining chemical perturbations with computational quantification of extrusion and cell density, we show that apoptosis is necessary but not sufficient for rosette formation, and that ERK1/2 signalling limits epidermal extrusion density. Furthermore, we find increased extrusion activity during starvation, and potential nutrient recycling via phagocytosis of extruded cells. Together, our findings indicate that epithelial cell extrusion has physiological roles in sea anemones and that its key hallmarks are likely evolutionarily ancient, predating the last common cnidarian-bilaterian ancestor.

DOI: https://doi.org/10.1038/s41467-026-74437-7
Nat Commun. 2026 Jun 19.

Conformational cycling of the Wntless transporter drives trafficking and secretion of Wnt morphogens.

Yunhui Ge, Taciani de Almeida Magalhaes, Hongjiang Wu, Dick J H van den Boomen, Thu Uyen Nguyen, Tongyi Dou, Gaya P Yadav, Sukyeong Lee, Zhao Wang, Andrew Lemoff, Xuemei Luo, Sumitha S Menon, Min Zhang, Jin Wang, Zhicheng Jin, Jiansen Jiang, Adrian Salic, Pengxiang Huang.

Wnt proteins are lipid-modified morphogens fundamental in development and disease. During Wnt biogenesis, the G-protein-coupled receptor (GPCR)-like transporter Wntless (WLS) escorts lipidated Wnts from the endoplasmic reticulum to the plasma membrane, then transfers them to extracellular carriers, forming active and soluble morphogen-carrier complexes. To dissect the mechanisms involved, we solve cryo-EM structures of Wnt-bound WLS and unliganded WLS, and perform structure-guided functional experiments. Wnts engage WLS via three conserved hairpins, which are all required for Wnt trafficking to the cell surface and carrier-mediated secretion. Wnt release from cells is driven by dramatic conformational changes in the WLS transmembrane domain, reminiscent of GPCR activation, together with WLS extracellular rearrangements. Unexpectedly, we find that Wnt5a bound to WLS forms dimers, with implications for Wnt signaling. These findings define the mechanism of WLS conformational cycling that governs the intracellular transport and extracellular release of Wnt morphogens, essential steps in the Wnt pathway.

DOI: https://doi.org/10.1038/s41467-026-74521-y
Nature. 2026 Jun 17.

Confined migration induces non-lethal DNA damage in developing neurons.

Zhejing Zhang, Andres Canela, Junko Kurisu, Peilin Zou, Takumi Kawaue, Naotaka Nakazawa, Noriko Takeda, Mai Saeki, Masaki Utsunomiya, Merve Bilgic, Fumiyoshi Ishidate, Gianluca Grenci, Takahiro Furuta, Yusuke Kishi, Hiroyuki Sasanuma, Mineko Kengaku.

Migratory cells tend to have soft nuclei that deform and penetrate narrow spaces1,2. Extensive nuclear deformation during migration can cause nuclear-envelope rupture and DNA damage in cancer cells, which may contribute to malignant transformation during tumour progression3-6. However, the importance of DNA damage in physiological migration is less well understood. Here we demonstrate that the migration of neurons in developing cerebral and cerebellar cortices is accompanied by massive DNA double-stranded breaks (DSBs) due to mechanostress during passage through narrow interstitial spaces. In contrast to many other migratory cells, these DSBs occur without detectable nuclear envelope rupture. Confined migration increases topoisomerase-IIβ covalently bound DSBs, and these lesions are repaired through non-homologous end-joining during brain development without causing cell death. Genome sequencing revealed that DSBs tend to occur at transcriptionally inactive regions. The deletion of ligase IV at the onset of neuronal migration leads to persistent DSB accumulation in cerebellar neurons with moderate transcriptional changes in genes related to synaptic function, neuronal development and stress and immune responses. The mutant mouse develops mild motor deficits in later life, suggesting that the DNA damage generated during normal brain development poses a potential disease risk if left unrepaired.

DOI: https://doi.org/10.1038/s41586-026-10648-8
Circulation. 2026 Jun 17.

Vacuolar H+-ATPase Preserves Cardiolipin Homeostasis Through the Lysosomal-Mitochondrial Axis to Restrain Cardiac Aging.

Hongtao Tie, Mengqian Hou, Yumeng Li, Min Pan, Dietbert Neumann, Ruimin Liu, Jun Zhang, Martijn F Hoes, Miranda Nabben, Jan F C Glatz, Xi Li, Xin Wu, Joost J F P Luiken, Shujin Wang.

   BACKGROUND: Cardiac aging involves progressive mitochondrial dysfunction, contributing to heart failure. Cardiolipin (CL), essential for mitochondrial function, is increasingly depleted in aging cardiomyocytes, promoting mitochondrial decline. Lysosomal degradation relies on v-ATPase (vacuolar-type H+-ATPase)-mediated acidification, and although lysosomes regulate phospholipid metabolism, their roles in CL homeostasis during aging remains unclear. This study examines whether v-ATPase dysfunction drives age-related cardiac changes by disrupting CL metabolism and mitochondrial function.
METHODS: To investigate underlying mechanisms and causality, we use RNA sequencing, targeted lipidomics, immunofluorescence microscopy, (co)immunoprecipitation, proximity ligation assays, subcellular fractionation, mitochondrial respiration analysis and echocardiography, a cardiolipin synthase-1 (Crsl1) knockout mouse model, and 2 v-ATPase knockout models. In addition, we assess whether a nutraceutical intervention targeting v-ATPase dysfunction can mitigate heart failure in aging mouse models and elderly people.
RESULTS: Our present findings reveal a sequence of events driving age-related cardiomyopathy: declining cardiac nicotinamide adenine dinucleotide levels impair v-ATPase-mediated lysosomal acidification by weakening the interaction between nicotinamide adenine dinucleotide-dependent glycolytic enzyme aldolase and v-ATPase. This disruption increases lysosomal membrane permeability by reducing lysosomal acidification, allowing cathepsin B to leak into mitochondria. There, cathepsin B disrupts mitochondrial CRLS1 (cardiolipin synthase I), impairing CL synthesis and remodeling. The resulting CL deficiency causes mitochondrial oxidative stress and programmed cell death, leading to mitochondrial and cardiac dysfunction. Genetic or chemical inhibition of v-ATPase and of CRLS1 in mouse models reproduce these age-related defects, highlighting their central roles in cardiac aging. Restoring nicotinamide adenine dinucleotide levels rescues lysosomal acidification and CL metabolism, protecting against age-related cardiomyopathy in rodents and humans.
CONCLUSIONS: Augmenting v-ATPase-mediated lysosomal acidification offers novel therapeutic strategies to combat age-related cardiomyopathy by rewiring CL homeostasis.

Keywords:  aged heart; cardiolipin metabolism; cardiolipin synthase 1; lysosomal acidification; mitochondrial homeostasis; vacuolar H+-ATPase

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.078376
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2601750123

Epithelial cells fire voltage spikes.

Sun-Min Yu, Steve Granick.

  Bioelectric signaling is well characterized in neurons and cardiomyocytes but remains largely unexplored in epithelia. Using multielectrode arrays, we demonstrate that localized laser injury to epithelial monolayers (primary human keratinocytes and MDCK cells) triggers voltage spikes in the range of 4 to 12 per min for over 60 min postinjury. These spikes exhibit depolarization, repolarization, and hyperpolarization phases lasting 1 to 2 s, a timescale three orders of magnitude slower than neuronal action potentials. Spike amplitudes and frequencies detected at 740 μm from the injury site (the maximum distance measured) are comparable to those at 140 μm and exhibit a nonmonotonic spatial profile, arguing against simple radial propagation from the wound. Calcium chelation with ethylenediaminetetraacetic acid abolishes spiking entirely, and inhibition of myosin II with blebbistatin produces equivalent suppression, indicating that calcium influx and actomyosin contractility are both required. The mechanosensitive channel modifier GsMTx4 partially suppresses spiking, implicating the role of stretch-activated ion channels. Most strikingly, pharmacological activation of the mechanosensitive channel TRPV4 and Piezo1 generates high-amplitude spikes (1 to 10 mV) even in the absence of injury, demonstrating that mechanosensitive channel activation is sufficient to drive epithelial electrical excitability. These findings reveal that epithelia, long thought to lack action-potential-like dynamics, possess intrinsic bioelectric excitability gated by mechanical stress, challenging the classical distinction that electrical signaling is exclusive to specialized tissues like neurons and muscles and suggesting a signaling modality for coordinating collective cellular responses across tissue-scale distances.

Keywords:  bioelectricity; epithelial; mechanosensitive ion channel keratinocyte; multielectrode array chip

DOI:  https://doi.org/10.1073/pnas.2601750123
Sci Adv. 2026 Jun 19. 12(25): eaec3505

NEDDylation maintains oocyte quality by stabilizing mitochondrial transcription.

Avery A Ahmed, Tessa E Steenwinkel, Bethany K Patton, Peixin Jiang, Matthew D Meyer, Jaspreet K Rishi, Mei Leng, Alexander B Saltzman, Elizabeth S Anaya, Momal Sharif, Laurie J McKenzie, Laura Detti, Anna Malovannaya, Sean M Hartig, Stephanie A Pangas.

Age-related decline in oocyte quality increases the risk of infertility, miscarriage, and birth defects. Mitochondrial dysfunction is a key contributor to this decline. Here, we report that oocyte-specific deletion of Uba3, which encodes the catalytic subunit of the E1 NEDDylation-activating complex, causes sterility in mice. Fully grown, germinal vesicle-stage Uba3 conditional knockout oocytes exhibit mitochondrial dysfunction, including elevated reactive oxygen species, impaired oxidative phosphorylation, and depletion of mitochondrially encoded RNA transcripts. Proteomic analysis identified alterations in mitochondrial-associated proteins, including enrichment of mitochondrial matrix and respiratory chain components and reduced abundance of electron transport chain complexes. These defects were associated with reduced levels of the mitochondrial RNA polymerase, POLRMT [polymerase (RNA) mitochondrial DNA directed]. We further show that POLRMT is directly modified by NEDDylation, which alters its stability by antagonizing ubiquitylation and degradation. Notably, NEDD8 levels decline with age in both mouse and human oocytes. Together, these findings identify NEDDylation as a regulator of oocyte quality and connect this pathway to mitochondrial transcription in oocytes.

DOI: https://doi.org/10.1126/sciadv.aec3505
Cell Rep. 2026 Jun 13. pii: S2211-1247(26)00635-2. [Epub ahead of print]45(6): 117557

Alternative 3' UTRs and RNA-binding proteins Ewsr1b, HuR, and Syncrip organize sequential waves of translation to drive embryonic development.

Keisuke Sato, Ludivine Fierro, Anyu Suginishi, Takahiro Sanada, Tomoya Kotani.

  Eggs of many species accumulate thousands of dormant mRNAs that are translated after fertilization at specific times and locations to direct development. However, how embryos coordinate translation of these mRNAs remains unclear. In this study, we identify sequential waves of translation critical for proper development progression. The first wave occurs within 1 h and includes translation of ewsr1b mRNA that harbors a short 3' untranslated region (UTR) comprising 16 nucleotides. The resulting Ewsr1b protein triggers the second translation wave through binding cytoplasmic mRNAs, including pou5f3, which encodes a transcription factor promoting zygotic genome activation. In contrast, HuR and Syncrip repress translation until the first and second waves, respectively. ewsr1b mRNA that has a long 3' UTR is translated in the second wave, and the 3' UTR's length determines protein localization and function. Overall, our findings reveal previously unknown molecular principles that coordinate translation timings and protein functions to drive long-term, multilayered processes.

Keywords:  3′ UTR; CP: developmental biology; CP: molecular biology; Ewsr1b; HuR; RNA granule; RNA-binding protein; Syncrip; embryo; subcellular compartment; translation; vertebrate

DOI:  https://doi.org/10.1016/j.celrep.2026.117557
Proc Natl Acad Sci U S A. 2026 Jun 23. 123(25): e2607264123

Diminished transcriptional activity and splicing changes drive gene length-biased rewiring in the aging transcriptome.

Saeid Parast, Madhurima Das, Yue He, Simai Wang, Sarah Gold, Benjamin Howard, Jacob Zeidner, Cassandra Philips, Issam Ben-Sahra, Vijay Ramani, Marta Iwanaszko, Ali Shilatifard.

  Transcription by RNA polymerase II (RNAPII), which is essential for protein-coding gene expression and cellular function, is increasingly understood to become dysregulated with aging. Here, we use a multimodal approach to comprehensively characterize age-dependent changes in RNAPII-mediated transcription in both mouse and human tissues. Short-read total RNA sequencing (RNA-seq) to profile nascent transcription reveals a global reduction in overall transcriptional activity/frequency in aged tissues, without apparent change in elongation rates. Transcriptomic analysis reveals a shift toward preferential expression of short genes in aged tissues, with notable upregulation of short stress-response genes and downregulation of long neurodevelopmental genes in the aged mouse brain. These results are recapitulated by analysis of total RNA-seq data from human tissues. Leveraging long-read RNA-seq, we determine that the representation of aberrant mono-exonic and intron-retention splice isoforms is increased in the aged mouse brain. Finally, we characterize the composition of RNAPII transcriptional machinery, finding that interactions between RNAPII and the Mediator complex are decreased in the chromatin of aged mouse liver and brain. Collectively, these analyses provide insight for future aging studies and reveal potential transcriptional control targets for anti-aging drug development.

Keywords:  RNA polymerase II; aging; chromatin; gene expression; transcription

DOI:  https://doi.org/10.1073/pnas.2607264123
Sci Adv. 2026 Jun 19. 12(25): eaed3887

Live imaging and multimodal profiling reveal transdifferentiation of a cochlear supporting cell subpopulation upon Notch inhibition.

Lama Khalaily, Shahar Kasirer, Rotem Domb, Mi Zhou, Buwei Shao, Shahar Taiber, Ran Elkon, Litao Tao, David Sprinzak, Karen B Avraham.

Regeneration enables organisms to repair damaged tissues, yet this capacity is notably limited in the cochlear sensory epithelium, essential for sound detection. A major cause of hearing loss arises from the irreversible loss of sensory hair cells (HCs) in the cochlea. While supporting cells (SCs) have a latent ability to transdifferentiate into HCs, this regenerative potential is rapidly lost after development. Using live imaging and single-cell multiomics of cochlear explants, we uncovered the cellular and molecular heterogeneity underlying the limited regenerative capacity of the neonatal mouse cochlea. Notch repression broadly silenced key SC genes, yet only a rare subpopulation of Deiters' cells (DC), termed transdifferentiating DCs (tDCs), initiated the transdifferentiation into HC fate. These cells underwent coordinated transcriptional and enhancer remodeling, linking epigenetic priming with morphological plasticity, while other SCs remained refractory despite robust Notch targets down-regulation. Our study provides a molecular definition of an early induced transitional DC to HC state, revealing Notch inhibition as a selective trigger that unmasks rare regenerative competence.

DOI: https://doi.org/10.1126/sciadv.aed3887
Cell Metab. 2026 Jun 15. pii: S1550-4131(26)00193-2. [Epub ahead of print]

The senescence-stiffening loop: Extracellular matrix remodeling, hypoperfusion, and mitochondrial dysfunction drive tissue aging.

Luigi Ferrucci, Stefano Donega, Allison B Herman, Rafael de Cabo, Myriam Gorospe.

  Aging tissues experience a gradual decline in perfusion and metabolic resilience due to complex interactions among extracellular matrix (ECM) remodeling, vascular dysfunction, and mitochondrial impairment. Stiffening of the ECM that results from collagen crosslinking, elastin loss, and basement membrane thickening reduces vascular compliance and impairs local angiogenesis. The consequent reduction in capillaries and diminished endothelial reactivity leads to ongoing or intermittent hypoxia, which triggers changes in transcriptomic and proteomic programs that inhibit oxidative phosphorylation and facilitate the production of reactive oxygen species. Under these conditions, mitochondria produce less ATP than is needed for homeostatic repair. This energetic breakdown triggers cellular senescence and inflammation, further increasing ECM stiffening, and thus creating a self-sustaining feedback loop that accelerates tissue aging and functional decline. Such a continuum from ECM stiffening to mitochondrial dysfunction may be considered a new therapeutic target for strategies aimed at maintaining vascular integrity, mitochondrial health, and cellular homeostasis during aging.

Keywords:  extracellular matrix; hypoperfusion; mitochondrial dysfunction; senescence

DOI:  https://doi.org/10.1016/j.cmet.2026.05.008
Nat Nanotechnol. 2026 Jun 15.

Programmed synthesis of mesoporous protein crystals in cellular reactors.

Hongru Yang, Dian-Zhao Lin, Zhe Li, Yuqing Yan, Zuo-Han Zhao, Byeongdu Lee, Chang Woo Song, Shunzhi Wang, Jiaxi Lu, Yimei Wang, Yongzhi Sun, Ken Livi, David Baker, Yayuan Liu, Dingchang Lin.

Protein crystals are naturally derived mesoporous materials with versatile structures and physicochemical properties. Here we introduce an intracellular synthesis platform that enables controllable and programmable protein crystallization. In live cells, we show that, after initial nucleation, steady protein expression governs crystal growth, yielding predictable, tunable dynamics in live cells. Exploiting this feature, we combined HaloTag and click chemistries to achieve modular, programmable immobilization of diverse guest materials with spatial patterning down to ~100 nm resolution. We further demonstrated the sequential release of immobilized materials in physiologically relevant fluids. As a proof of concept, we programmed particles to carry human fibroblast growth factors in distinct layers, which elicited designed oscillatory Akt signalling patterns in cell culture. This work outlines a programmable method for producing mesoporous materials, with possible applications in catalysis and biomedicine.

DOI: https://doi.org/10.1038/s41565-026-02198-x
Mol Cell. 2026 Jun 19. pii: S1097-2765(26)00385-0. [Epub ahead of print]

LRRC58 defines an E3 ubiquitin ligase complex sensitive to cysteine abundance.

Dylan E Ramage, Lianne H E Wieske, Charlotte Crowe, Jens B Christensen, Theo A von Wilmowski, Zoe Bannister, Drew W Grant, Mark A Nakasone, Kevin Haubrich, Mark Dorward, Iva A Tchasovnikarova, Michael P Weekes, Nicholas J Matheson, N Sumru Bayin, Alessio Ciulli, Richard T Timms.

  Adaptation to fluctuating nutrient supply is essential for organismal survival, but how human cells monitor the abundance of many critical nutrients remains undefined. Characterizing the conditional degradation of CDO1, the critical enzyme responsible for cysteine catabolism, here we identify a Cullin-RING E3 ligase complex defined by the substrate adaptor LRRC58 that is sensitive to cysteine abundance. When cysteine is replete, LRRC58 activity is restrained through ubiquitination and proteasomal degradation. Upon cysteine deprivation, LRRC58 is stabilized to permit CDO1 degradation. Through saturation mutagenesis stability profiling, we systematically validate a structural model of the CDO1-LRRC58 interaction and identify residues at the LRRC58 C terminus required for cysteine-dependent instability. CDO1 degradation prevents ferroptotic cell death upon cysteine scarcity, and CDO1 mutations causing neurodevelopmental defects in humans encode dominant-active proteins refractory to LRRC58 recognition. Altogether, these data reveal the CDO1-LRRC58 axis as a critical regulator of cysteine homeostasis that safeguards neural development.

Keywords:  CDO1; Cullin-RING E3 ligase; LRRC58; amino acid sensing; conditional protein degradation; cysteine; cysteine catabolism; ferroptosis; ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.molcel.2026.06.014
Cell Chem Biol. 2026 Jun 18. pii: S2451-9456(26)00186-8. [Epub ahead of print]33(6): 748-766

Mechanisms and interventions of epigenetic aging.

Qingqing Chu, Yihang Li, Zeming Wu, Jing Qu, Guang-Hui Liu.

  Increasing evidence suggests that epigenetic dysregulation is both a hallmark and a potential driving force of aging. As a multifactorial, non-linear, and systemic biological process, aging likely results from a progressive imbalance in a complex epigenetic network involving DNA, histones, RNA, and non-coding sequences. These interconnected alterations collectively lead to core aging features such as genomic instability, heightened inflammation, and loss of cellular identity. In this review, we highlight the central role of epigenetic mechanisms across different dimensions in cellular, tissue, and organismal aging. Furthermore, we discuss potential intervention strategies designed to counteract these epigenetic alterations, indicating both their promise and the associated challenges.

Keywords:  age-related diseases; aging; epigenetic mechanisms; interventions; senescence

DOI:  https://doi.org/10.1016/j.chembiol.2026.05.007
Nat Commun. 2026 Jun 16.

Meiotic pairing through barcode-like satellite DNA repeats.

Lena Skrutl, Ankita Chavan, Anna Sintsova, Ilaria Ceppi, Corin J Ropp, Shinichi Sunagawa, Petr Cejka, Madhav Jagannathan.

During meiosis, chromosomes must find, pair, and synapse with their homologous partners in the crowded milieu of the nucleus. Although homology detection generally relies on recombination, pairing can occur in its absence, suggesting alternative mechanisms. Here, we show that the barcode-like arrangement of non-coding satellite DNA repeats facilitates homologue pairing during meiosis. Using satellite DNA deletion, duplication, and translocation strains, we demonstrate that repeat mismatches perturb meiotic pairing, particularly at centromeres and pericentromeres. Notably, pairing defects are also observed in the progeny of D. melanogaster natural populations that have diverged in their satellite DNA content. In the absence of satellite DNA homology, pairing is antagonised by the HORMAD protein, Mad2, while a Pachytene checkpoint 2 (Pch2)-dependent meiotic delay restores pairing. In addition, compromised meiotic pairing is strongly correlated with mid-oogenesis cell death, a quality control mechanism that likely culls defective oocytes to prevent chromosome mis-segregation and aneuploidy. Taken together, our findings reveal an important role for satellite DNA repeats during meiotic homology detection. We propose that this repeat-based pairing mechanism exerts an underappreciated selective pressure, constraining the divergence of rapidly evolving satellite DNA within interbreeding natural populations.

DOI: https://doi.org/10.1038/s41467-026-74398-x
Cell Metab. 2026 Jun 17. pii: S1550-4131(26)00222-6. [Epub ahead of print]

Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis.

Jinbao Ye, Qianyi Wan, Xingzhu Liu, Yawen Deng, Zehong Zhang, Haiou Chen, Chaoxin Gao, Shiyu Zhang, Yuedan Zhu, Jinhua Yan, Yu Yuan, Yi Chen, Haiyang Chen.

  The liver is known to play a pivotal role in modulating blood glucose homeostasis through intrahepatic glucose metabolism. Here, we reveal a unique mechanism by which fatty liver exacerbates hyperglycemia through remote communication from hepatocytes to intestinal stem cells (ISCs), independent of enhanced intrahepatic gluconeogenesis. Mechanistically, hepatocyte-derived alkaline phosphatase (ALP) targets α2δ-1 in ISCs to promote the membrane translocation of Cav1.2. This process triggers increased intracellular calcium levels, which subsequently activates the calcineurin/NFATC2 signaling axis, thereby inhibiting SOX21 expression. Then, decreased expression of SOX21 downregulated bone morphogenetic protein 7 (BMP7), ultimately hindering ISCs differentiation into intestinal L-cells. Consequently, the levels of hypoglycemic enteroendocrine hormones secreted by L-cells are decreased, thereby promoting hyperglycemia. Therapeutically, inhibiting ALP synthesis in fatty liver independently reduces blood glucose and synergistically enhances the hypoglycemic effect of metformin. Our study highlights the role of liver-gut communication in regulating the fate of ISC differentiation and blood glucose homeostasis.

Keywords:  SOX21; alkaline phosphatase; blood glucose; fatty liver; intestinal stem cells

DOI:  https://doi.org/10.1016/j.cmet.2026.05.012
Cell Metab. 2026 Jun 16. pii: S1550-4131(26)00221-4. [Epub ahead of print]

FGF21 reduces ER stress by enhancing the unfolded protein and integrated stress responses through increased sulfide signaling.

Gerald Grandl, Ann-Christine König, Fabian Metzger, Arkadiusz Liskiewicz, Tanja Hefele, Shelly Nason, Aaron Novikoff, Nada Al-Refaie, Md Abdur Rahman, Ahmed Khalil, Qian Zhang, Gustav Collden, Brian Finan, Jonathan Douros, Kirk Habegger, Alberto Cebrian-Serrano, Stefanie M Hauck, Matthias H Tschöp, Timo D Müller.

  Fibroblast growth factor 21 (FGF21) is an endocrine hormone with broad metabolic actions at supraphysiological concentrations but unclear physiological function, related to endoplasmic reticulum (ER) stress. ER stress activates the unfolded protein response (UPR), a cellular repair mechanism that maintains cellular homeostasis during protein folding stress. Using proximity labeling, we assessed the intracellular action of FGF21 at its receptor β-klotho (KLB) and discovered associations with protein folding in the ER, ER stress, and H2S production. We found that FGF21 increases enzymatic sulfide production and enhances, but does not initiate, the UPR. This FGF21 action is blunted by genetic or pharmacological inhibition of sulfide signaling and is phenocopied by an H2S donor in vivo. FGF21 modulating the UPR requires KLB, and even physiological levels of FGF21 modulate the UPR via increased hepatic H2S production. Collectively, we reveal a novel physiological role of FGF21 as an endocrine stress hormone that enhances the UPR via increased sulfide signaling.

Keywords:  ER stress; FGF21; H(2)S; ISR, β-klotho, KLB; UPR; integrated stress response; sulfide signaling; unfolded protein response

DOI:  https://doi.org/10.1016/j.cmet.2026.05.011
Nat Commun. 2026 06 17. pii: 5359. [Epub ahead of print]17(1):

Reverse engineering of BNIP3 identifies a mitochondrial protective peptide.

Ulrike B Hendgen-Cotta, Anna Roth, Christine Beuck, Daniel Messiha, Stephan Settelmeier, Shah Bahrullah Shah, Sebastian Korste, Kenny Bravo-Rodriguez, Mike Blueggel, Feyza Cansiz, Luiza Martins Nascentes Melo, Jonas Roesler, Sven W Meckelmann, Oliver J Schmitz, Farnusch Kaschani, Markus Kaiser, Sonja Esfeld, Omar El Bounkari, Jürgen Bernhagen, Sophie Brameyer, Kirsten Jung, Linda-Isabell Schmitt, Markus Leo, Tim Hagenacker, Matthias Totzeck, Thomas Minor, Michael Ehrmann, Alpaslan Tasdogan, Peter Bayer, Tienush Rassaf.

Recent advances in mitochondrial network dynamic and signalling highlight mitochondria as key therapeutic targets across diverse diseases. Yet, high drug development failure rates reflect an incomplete understanding of upstream molecular regulators of mitochondrial fate. Here, we address this gap by reverse engineering of the BH3-only protein BNIP3. Structural modelling and sequence-function analyses of its N-terminus identify a critical functional domain and amino acid hotspots that directly activate BCL-2 executioner proteins, triggering mitochondrial cell death. Leveraging these insights, we develop a BNIP3 antagonist peptide (B-017) that disrupts interactions between BNIP3 and BCL-2 executioner proteins, preserving mitochondrial integrity. B-017 demonstrates target specificity, a favourable safety profile, and robust suppression of cell death signalling in human cells. In clinically relevant animal models, it reduces tissue damage in the heart, brain, and liver. Together, these findings position B-017 as a promising therapeutic candidate targeting mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-73993-2