bims-pideca 2026-06-28 papers

bims-pideca

Biomed News

on Class IA PI3K signalling in development and cancer

Issue of 2026–06–28
seventeen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU

Structures of the PI3Kα/KRas complex on lipid bilayers reveal molecular mechanisms of PI3Kα activation.
ParTIpy: a scalable framework for archetypal analysis and Pareto task inference.
AKT-mediated phosphorylation of ZDHHC5 promotes NOD1 palmitoylation and innate immune signaling.
Renal vein thrombosis as a reversible vascular renal complication of CLOVES syndrome: a case report.
YIF1A activates mTORC1 signaling to promote cellular senescence.
Alternate RNA decoding results in stable and abundant proteins in mammals.
mTOR Substrate Phosphorylation in Growth Control: An Update.
Functional characterization of PIK3CA E545A mutation in MCF-7 breast cancer cells reveals enhanced proliferation and resistance to Alpelisib.
Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.
Skin capillary endothelial cells form a network of spatiotemporally conserved Ca2+ activity.
High-resolution 3D chromatin maps reveal PTEN enhancer hubs bridged to the promoter through flanking anchors.
Physiological media and oxygen levels modulate cancer hallmarks in cultured breast cancer cells.
Allostery is a widespread cause of loss-of-function variant pathogenicity.
SGLT2 Inhibitors Promote Diabetic Wound Healing Via AMPK/AKT/mTORC1-Regulated Endothelial Angiogenesis.
MYDGF promotes pathological and physiological retinal angiogenesis via the Gαi1/3-Gab1-Akt-mTOR signaling.
Targeting developmental reprogramming: hPSC insights for cancer interception.
Exosomal Oleic Acid Promotes Lymphangiogenesis and Nodal Metastasis in Cervical Cancer via the AKT/mTOR Pathway.

Mol Cell. 2026 Jun 25. pii: S1097-2765(26)00381-3. [Epub ahead of print]

Structures of the PI3Kα/KRas complex on lipid bilayers reveal molecular mechanisms of PI3Kα activation.

Hayarpi Torosyan, Michael D Paul, Brigitte G Meyer, Allison Maker, Natalia Jura, Kliment A Verba.

  PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras. To understand the molecular mechanism of PI3Kα activation, we used cryo-electron microscopy to visualize the conformational states that underlie its transition to an active signaling complex. Here, we present structures of the PI3Kα/KRas complex embedded in lipid nanodiscs, revealing a rich ensemble of PI3Kα conformations that capture the progressive release of key inhibitory domains from the PI3Kα catalytic core. PIP2 triggers significant restructuring of active site regulatory motifs while an activating phosphopeptide induces dimerization of the PI3Kα/KRas complex through a p110α catalytic subunit-mediated interface that is sterically occluded in autoinhibited PI3Kα. In cells, dimeric PI3Kα amplifies Akt signaling in response to growth factor stimulation. Collectively, these structures map the conformational landscape of PI3Kα activation and reveal previously unexplored interfaces for potential therapeutic targeting.

Keywords:  PI3K; PIP2; Ras; cryo-EM; nanodisc; p110; p85; phosphotyrosine; signaling; signalosome

DOI:  https://doi.org/10.1016/j.molcel.2026.06.010
Mol Syst Biol. 2026 Jun 25.

ParTIpy: a scalable framework for archetypal analysis and Pareto task inference.

Philipp Sven Lars Schäfer, Leoni Zimmermann, Paul L Burmedi, Avia Walfisch, Noa Goldenberg, Shira Yonassi, Einat Shaer Tamar, Miri Adler, Jovan Tanevski, Ricardo O Ramirez Flores, Julio Saez-Rodriguez.

Trade-offs between different tasks are pervasive across scales in biological systems. For example, cells cannot perform all possible functions simultaneously; instead they allocate limited resources to specialize in subsets of tasks by activating specific gene expression programs. Pareto Task Inference (ParTI) is a framework for analyzing biological trade-offs grounded in multi-objective optimality. However, existing software for ParTI neither scales to large datasets nor integrates well with standard data analysis workflows. To address this gap, we developed ParTIpy ( https://pypi.org/project/partipy ), an open-source Python package that leverages optimization and coreset methods to scale archetypal analysis, the core algorithm underlying ParTI, to millions of cells. By providing tools to characterize archetypes and comprehensive documentation ( https://partipy.readthedocs.io ), ParTIpy integrates seamlessly into existing analysis workflows, especially for single-cell data. We demonstrate how ParTIpy can be used to study intra-cell-type gene expression variability through the lens of task allocation, offering a principled alternative to methods that impose discrete cell state classifications on inherently continuous variation.

DOI: https://doi.org/10.1038/s44320-026-00209-6
Front Immunol. 2026 ;17 1819627

AKT-mediated phosphorylation of ZDHHC5 promotes NOD1 palmitoylation and innate immune signaling.

Shaojie Mi, Yue Zhu, Qian Li, Xin Wang, Xuewu Guo, Yali Chen.

   Introduction: Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular pattern recognition receptor that detects bacterial peptidoglycan and initiates innate immune responses through membrane-associated signaling complexes. NOD1 activation depends on ZDHHC5-mediated palmitoylation, which promotes its membrane recruitment. However, whether growth factors and insulin modulate this NOD1 activation remains poorly defined.
Methods: We investigated the effects of growth factors and insulin on NOD1 signaling using biochemical and cell-based approaches. Protein phosphorylation and interactions were analyzed by immunoblotting, co-immunoprecipitation, and mutagenesis assays. NOD1 palmitoylation, membrane localization, and downstream signaling activities were evaluated following modulation of AKT signaling and ZDHHC5 phosphorylation.
Results: We found that growth factors and insulin positively regulate NOD1 activation through an AKT-ZDHHC5-NOD1 signaling axis. Mechanistically, AKT directly phosphorylated the palmitoyltransferase ZDHHC5 at Ser345 and Ser380, promoting its retention at the plasma membrane and enhancing its enzymatic activity toward NOD1. AKT-dependent phosphorylation increased NOD1 palmitoylation and membrane recruitment, thereby facilitating activation of downstream innate immune signaling pathways.
Discussion: These findings identify a previously unrecognized mechanism linking growth factor- and insulin-mediated AKT activation to innate immune signaling. AKT-dependent phosphorylation of ZDHHC5 promotes NOD1 palmitoylation and activation, revealing a positive regulatory axis that integrates metabolic cues with innate immune responses. The AKT-ZDHHC5 pathway may therefore represent a potential target for modulating NOD1- driven inflammatory diseases.

Keywords:  AKT; NOD1 signaling; ZDHHC5; growth factor signaling; palmitoylation; phosphorylation

DOI:  https://doi.org/10.3389/fimmu.2026.1819627
CEN Case Rep. 2026 Jun 23. pii: 105. [Epub ahead of print]15(4):

Renal vein thrombosis as a reversible vascular renal complication of CLOVES syndrome: a case report.

Zeynep Ural.

  PIK3CA-related overgrowth spectrum (PROS) comprises mosaic gain-of-function variants in PIK3CA that lead to segmental overgrowth and complex vascular malformations. Renal involvement has been inconsistently described and mainly includes glomerulomegaly and focal segmental glomerulosclerosis. We report a 39-year-old woman with a phenotypic diagnosis of CLOVES syndrome molecularly supported by a somatic mosaic PIK3CA variant, NM_006218.4:c.1634 A > C, p.Glu545Ala, detected in affected hypertrophic tissue. She presented with acute kidney injury and subnephrotic-range proteinuria secondary to left renal vein thrombosis. Imaging revealed intrarenal venous congestion in the setting of extensive abdominal venous malformations. Anticoagulation resulted in complete radiologic and functional recovery. Renal vein thrombosis should be considered as a potentially reversible vascular cause of acute kidney injury and proteinuria in patients with CLOVES syndrome/PROS, particularly in the presence of extensive venous malformations.

Keywords:  CLOVES; PIK3CA; Proteinuria; Renal Vein Thrombosis; Vascular malformation

DOI:  https://doi.org/10.1007/s13730-026-01149-8
Cell Death Dis. 2026 Jun 23.

YIF1A activates mTORC1 signaling to promote cellular senescence.

Xiaogang Zhang, Luying Liu, Mengdi Shang, Bin Hu, Shu Zhu, Xi Wang, Jieying Liu, Yanchun Han, Xiaodan Wei, Qi Cao, Fan Li, Lijie Gao, Jingyu Sun, Jiaqi Yu, Chentai Tan, Menghua Dong, Tie-Shan Tang, Jiu-Qiang Wang.

The mechanistic target of rapamycin complex 1 (mTORC1) serves as a central metabolic hub that integrates nutrient signals and orchestrates cellular metabolism to regulate many fundamental cell processes. While mTORC1 activation is known to occur both on lysosomal membranes and at the Golgi apparatus in response to environmental cues, the molecular mechanisms governing its Golgi-associated activation remain poorly understood. In this study, we identified YIF1A as a novel Golgi-localized regulator of growth factor-mediated mTORC1 signaling. Mechanistically, YIF1A interacted with the E3 ubiquitin ligase RNF126 to facilitate K48-linked polyubiquitination of G3BP1/2, thereby promoting mTORC1 activation. Genetic depletion of either YIF1A or RNF126 stabilized G3BP1/2 proteins and significantly impaired mTORC1 activity. Notably, YIF1A knockdown conferred resistance to etoposide- and doxorubicin-induced cellular senescence. The evolutionary conservation of this pathway was demonstrated by extended or shortened lifespan in Caenorhabditis elegans lacking or overexpressing yif-1, the invertebrate ortholog of YIF1A. Our findings not only elucidate a previously unrecognized Golgi-specific regulatory axis for mTORC1 activation but also suggest YIF1A as a potential therapeutic target for modulating aging-related pathologies.

DOI: https://doi.org/10.1038/s41419-026-09034-z
Nature. 2026 Jun 24.

Alternate RNA decoding results in stable and abundant proteins in mammals.

Shira Tsour, Rainer Machné, Andrew Leduc, Simon Widmer, Eunice Koo, Jeremy Guez, Konrad J Karczewski, Nikolai Slavov.

Amino acid substitutions may substantially alter protein stability and function1,2. However, the contribution of substitutions that arise from alternate translation (deviations from the genetic code) is unknown. Here to address this issue, we analysed deep proteomic, transcriptomic and genomic data from more than 1,000 human samples, including 6 cancer types and 26 healthy human tissues. This global analysis identified 60,803 fragmentation spectra corresponding to 8,746 unique substitutions in proteins derived from 1,767 genes, including 1,955 confidently localized sites. Some substitutions were shared across samples, whereas others exhibited strong tissue-type and cancer specificity. Notably, products of alternate translation were more abundant than their canonical counterparts for hundreds of proteins, which suggests that there is sense-codon recoding. Recoded proteins included transcription factors, proteases, signalling proteins and proteins associated with neurodegeneration. Mechanisms that contribute to substitution abundance included protein stability, codon frequency, codon-anticodon mismatches and RNA modifications. We also characterized how alternatively translated proteoform ratios vary across protein domains, tissue types and cancers. These ratios were positively associated with intrinsically disordered regions and genetic polymorphisms in the gnomAD database, although the polymorphisms could not account for the substitutions. The sequence, relative abundance and the tissue specificity of alternatively translated proteins were conserved between humans and mice. These results demonstrate the contribution of alternate translation to the diversification of mammalian proteomes and its association with protein stability, tissue-specific proteomes and disease.

DOI: https://doi.org/10.1038/s41586-026-10678-2
Cancers (Basel). 2026 Jun 15. pii: 1944. [Epub ahead of print]18(12):

mTOR Substrate Phosphorylation in Growth Control: An Update.

Don Benjamin, Michael N Hall.

  Background: The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine protein kinase that integrates inputs on nutrient status, energy levels, and growth factor stimulation to accordingly regulate cell growth and metabolism. It does this by activating or repressing target proteins covering a broad array of cellular processes. mTOR nucleates two structurally and functionally distinct protein complexes, mTORC1 and mTORC2. Because of their wide-ranging effects in the cell, both mTOR complexes are presumed to have a large number of targets. However, only a relatively small number have been conclusively identified. Methods: With emphasis on mammalian mTOR, we previously reviewed the extensive mTOR literature (1991-2021) and compiled a list of all reported substrates of mTORC1 and mTORC2. We have updated this list for the period 2022-2025. Results/Conclusions: Many of the targets are involved in autophagy, underscoring the major role of mTOR in the regulation of this process. From the perspective of this Special Issue, targets linked to cancer may be responsible for executing an mTOR-driven pro-oncogenic program and merit future study.

Keywords:  autophagy; cancer; cell signaling; mTOR; metabolism; phosphorylation

DOI:  https://doi.org/10.3390/cancers18121944
Biochem Biophys Res Commun. 2026 Jun 24. pii: S0006-291X(26)00953-8. [Epub ahead of print]829 154189

Functional characterization of PIK3CA E545A mutation in MCF-7 breast cancer cells reveals enhanced proliferation and resistance to Alpelisib.

Hoai Thu Le, Nguyen Bao Nghi, Vu Diem My, Hoang Anh Vu, Ma Chi Thanh, Bui Minh Tri, Vo Van Thanh Niem, Huynh Anh Phuong.

  PIK3CA mutations are central oncogenic drivers in hormone receptor-positive, HER2-negative breast cancer; however, the functional and therapeutic relevance of noncanonical variants remains incompletely defined. The E545A mutation, increasingly reported in specific patient populations, has not been systematically investigated. We generated an isogenic MCF-7 cell model harboring the PIK3CA E545A mutation using CRISPR/Cas9-mediated homology-directed repair to delineate its phenotypic and pharmacological consequences. E545A induced a robust gain-of-function phenotype, characterized by a mesenchymal-like morphological transition with reduced circularity and decreased cell size. This structural shift was accompanied by enhanced tumor cell fitness, including accelerated proliferation kinetics, increased metabolic activity, and significantly elevated clonogenic capacity compared with wild-type controls. Notably, growth trajectories showed sustained divergence between mutant and control cells across all time points, indicating a stable proliferative advantage. Importantly, E545A conferred diminished sensitivity to the PI3Kα inhibitor Alpelisib. Mutant cells retained migratory capacity under treatment and exhibited a pronounced, time-dependent increase in IC50, consistent with adaptive resistance. Collectively, these findings identify E545A as a functionally active and therapeutically consequential PIK3CA variant. Our study expands the current understanding of PIK3CA-driven oncogenic diversity beyond canonical hotspot mutations and underscores the need for variant-resolved stratification to improve the efficacy of PI3K-targeted therapies.

Keywords:  Alpelisib; Breast cancer; CRISPR/Cas9; E545A; PIK3CA

DOI:  https://doi.org/10.1016/j.bbrc.2026.154189
Sci Signal. 2026 Jun 23. 19(943): eadw1017

Diacylglycerol kinase ζ in B lymphocytes supports CD40-mediated immune synapse formation, mTORC1 signaling, and plasma cell fate.

Ana Fernández-Barrecheguren, Adrián Fernández-Rego, Lucía Fuentes-Cantos, Tirso Pons, Belén S Estrada, Marta Iborra-Pernichi, María Velasco de la Esperanza, Tahmineh Ebrahimi, Ana Sagrega-Aparisi, Sara Cogliati, Nuria Martínez-Martín, Rodrigo Jiménez-Saiz, Yolanda R Carrasco.

To mount a robust T cell-dependent immune response, antigen-specific B lymphocytes require the stimulation of the transmembrane receptor CD40 through immune synapse formation with CD4+ T follicular helper cells. CD40 stimulates the activation of mammalian target of rapamycin complex 1 (mTORC1) and remodels mitochondria to meet the increased bioenergetic and anabolic demands of activated B cells. Here, we found that diacylglycerol kinase ζ (DGKζ) supported mTORC1 activation downstream of CD40 stimulation in mouse B cells. We showed that DGKζ was required for organellar translocation to the CD40-mediated immune synapse and for the recruitment of mTORC1 to lysosomes, the latter of which was necessary for mTORC1 activation and function. The production of phosphatidic acid by DGKζ was crucial for these processes. DGKζ-/- B cells exhibited defects in protein biosynthesis, metabolite transporter expression, and cell cycle progression, together with dysregulation of the transcriptional network that determines B cell fate. To sustain their bioenergetic and metabolic demands, DGKζ-/- B cells enhanced their mitochondrial function. Together, these effects of DGKζ loss led to decreases in germinal center responses and in the generation of long-lived plasma cells and memory B cells in mice. Thus, our data identify DGKζ as an essential mediator of CD40 functions in the B cell immune response.

DOI: https://doi.org/10.1126/scisignal.adw1017
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2519708123

Skin capillary endothelial cells form a network of spatiotemporally conserved Ca2+ activity.

Anush Swaminathan, David G Gonzalez, Catherine Matte-Martone, Fei Xu, Deandra Simpson, Jessica L Moore, Zhongqi Lin, Ushnish Rana, David Monedero-Alonso, Julia J Mack, Chen Yuan Kam, Valentina Greco.

  Ca2+ signaling and its regulation are important for endothelial cell (EC) function and signaling. Yet, the spatiotemporal organization of Ca2+ activity and its regulation across a vascular plexus is poorly understood in an in vivo mammalian context. To overcome this gap in knowledge, we developed an intravital imaging approach to resolve Ca2+ activity with single-cell resolution in skin vasculature of adult mice via multiphoton microscopy. Here, we tracked thousands of Ca2+ events in the skin capillary plexus during homeostasis and observed signaling heterogeneity between ECs, with just over half displaying Ca2+ activity at any given time. Longitudinal tracking of the same mice revealed that the same capillary ECs maintain Ca2+ activity over days to weeks. Interestingly, activity dynamics, such as frequency and event duration, are not conserved at a single-cell level but are maintained at an EC population level. Molecularly, conditional deletion of the gap junction protein Connexin 43 (Cx43cKO) in ECs leads to a subset of ECs displaying sustained Ca2+ activity, biasing signaling dynamics of the whole network toward chronically persistent activity over time. Sustained capillary Ca2+ activity results in vascular permeability and flow dysregulation. Last, through pharmacological targeting of known agonists/antagonists, we showed that inhibition of L-type Voltage Gated Ca2+ channels non-cell-autonomously restores Ca2+ activity, blood flow, and barrier function in Cx43cKO mice. Collectively, our work provides insight into the spatial and temporal characteristics, extent, and regulation of Ca2+ activity in skin capillaries of live mice.

Keywords:  Ca2+ signaling; live imaging; vascular biology

DOI:  https://doi.org/10.1073/pnas.2519708123
Commun Biol. 2026 Jun 25.

High-resolution 3D chromatin maps reveal PTEN enhancer hubs bridged to the promoter through flanking anchors.

Thibaut Matis, Elodie Darbo, Jessica Baud, Noé Calais-Yager, Delfine Lafon, Valérie Prouzet-Mauléon, Sandrine Dabernat, Michel Longy, Nicolas Sévenet.

Understanding the cis-regulatory architecture of tumor suppressor loci is crucial for elucidating the mechanisms of gene dysregulation in cancer and genetic syndromes. Despite its central role in multiple cancers and PTEN Hamartoma Tumor Syndrome (PHTS), the regulatory landscape of the PTEN locus remains largely uncharacterized. Using high-resolution Tiled-C and multi-omics profiling across 11 human cell lines, including two patient-derived models, we map a 3 Mb region surrounding the PTEN topologically associated domain (TAD). We identify seven chromatin hubs anchoring eleven enhancers, whose CRISPR interference substantially reduces PTEN expression. In these hubs, most enhancers preferentially interact with each other rather than the PTEN promoter, forming a spatially organized enhancer network. Notably, enhancers are not in direct contact with the promoter but are brought into proximity through associated flanking chromatin anchor points enriched in REX elements, enabling gene regulation by bridging distal regulatory elements. Lastly, while structural variants can disrupt TAD, PTEN mutations alone only slightly reinforce intra-TAD contacts without changing the structure. These findings provide the first high-resolution map of PTEN enhancer hubs, reveal new principles of enhancer cooperation and long-range gene regulation, and delineate candidate regions whose disruption may contribute to PHTS and PTEN-driven tumorigenesis.

DOI: https://doi.org/10.1038/s42003-026-10533-0
FEBS J. 2026 Jun 21.

Physiological media and oxygen levels modulate cancer hallmarks in cultured breast cancer cells.

Jacob E Wiebe, Ricardo Alva, Fereshteh Moradi, Sarah Alderman, Ping Liang, Jeffrey A Stuart.

  The concepts of physioxia and physiological media for mammalian cell culture have gained attention over the past several years. Although the effects of oxygen tension or nutrient composition have been examined individually, their combined, large-scale impacts on cancer cell biology remain poorly understood. Here, we integrated transcriptomic, proteomic, and functional analyses to assess how oxygen levels (18% vs. 5% O2) and medium composition (DMEM vs. Plasmax) influence human breast cancer (MCF7) cells. We found that culturing MCF7 cells in physioxia (5% O2) and Plasmax medium induces a transcriptional profile that more closely resembles breast tumors in vivo. Moreover, changes in transcript and protein abundance were significantly associated with cellular growth, motility, and metabolism. At the functional level, oxygen level and culture medium affected proliferation, migration, glucose consumption, and metabolic activity in MCF7 cells. We conclude that both oxygen levels and medium composition in culture modulate hallmark cancer phenotypes, underscoring the importance of mimicking physiological microenvironments when studying biological mechanisms and therapeutic approaches in cancer.

Keywords:  cancer cells; cell culture; culture media; oxygen; physiological cell culture; proteomics; transcriptomics

DOI:  https://doi.org/10.1111/febs.70629
Nat Commun. 2026 Jun 22.

Allostery is a widespread cause of loss-of-function variant pathogenicity.

Xiaotian Liao, Ben Lehner.

Allosteric communication between non-contacting sites in proteins plays a fundamental role in biological regulation and drug action. While allosteric gain-of-function variants are known drivers of oncogene activation, the broader importance of allostery in genetic disease and protein evolution is less clear. Here, we introduce a comparative framework that disentangles functional disruption by mutations from protein destabilization. Applying this framework across diverse datasets-ranging from paired experimental measurements of abundance and activity to proteome-wide comparisons of evolutionary fitness and biophysical stability predictions-we provide evidence that allostery is a widespread cause of loss-of-function variant pathogenicity in human genetic diseases. In addition, our analyses reveal a conserved distance-dependent decay of allosteric mutational effects outside of protein active sites. As an important mechanism of pathogenicity, allostery needs to be better mapped, understood, and predicted across the human proteome.

DOI: https://doi.org/10.1038/s41467-026-74517-8
Arterioscler Thromb Vasc Biol. 2026 Jun 25.

SGLT2 Inhibitors Promote Diabetic Wound Healing Via AMPK/AKT/mTORC1-Regulated Endothelial Angiogenesis.

Furkan Bestepe, George F Ghanem, Caroline Kelly, Kamran Huseynli, Danielle V Richards, Rachel Barber, Annabelle Zamary, Parul Sahu, Payam Salehi, Gordon S Huggins, Basak Icli.

   BACKGROUND: Approximately 25% of patients with type 2 diabetes are at risk of developing diabetic ulcers, which can progress to amputations. A key challenge in diabetic wound healing is impaired angiogenesis. Although SGLT2 (sodium-glucose transporter 2) inhibitors are known for their cardiovascular and renal benefits, their role in wound healing and angiogenesis, remains incompletely understood.
METHODS: We evaluated the effects of empagliflozin, dapagliflozin, and canagliflozin on wound healing in db/db mice by measuring wound closure, granulation tissue thickness, and perfusion. Angiogenesis and proliferation were assessed by CD31 and Ki67 immunostaining. Ex vivo studies used human skin organoids, sprouting assays from human microvessels and murine aortic explants. In vitro studies were performed in human umbilical vein endothelial cells (ECs).
RESULTS: Empagliflozin and dapagliflozin significantly improved wound healing, perfusion, angiogenesis, and cell proliferation while canagliflozin showed limited benefit. In human skin organoids and ECs, empagliflozin and dapagliflozin but not canagliflozin improved wound closure, angiogenesis, proliferation, and migration. Sprouting angiogenesis of human vascular explants and mice aorta showed significantly increased branching and junction formation in response to empagliflozin and dapagliflozin. All 3 SGLT2 inhibitors similarly suppressed inflammation and improved EC barrier function, while empagliflozin and dapagliflozin selectively increased tissue remodeling gene expression. Mechanistically, canagliflozin significantly increased AMPK (AMP-activated protein kinase) phosphorylation while decreasing AKT/mTORC1 (mechanistic target of rapamycin complex 1) activation compared with empagliflozin, dapagliflozin. AMPK inhibition with compound C, or dose reduction of canagliflozin, partially restored AKT/mTORC1 signaling and wound closure.
CONCLUSIONS: These findings uncover distinct angiogenic effects among SGLT2 inhibitors. Empagliflozin and dapagliflozin promote EC-angiogenic functions through balanced AMPK/AKT/mTORC1 signaling, whereas canagliflozin impaired these processes via excessive AMPK activation and suppression of AKT/mTORC1 signaling. AMPK inhibition or dose reduction restored AKT/mTORC1 signaling and partially rescued wound healing, underscoring the importance of balanced AMPK/AKT/mTORC1 signaling for EC-angiogenic function in diabetic wounds.

Keywords:  AMP-activated protein kinases; TOR serine-threonine kinases; angiogenesis; canagliflozin; dapagliflozin; empagliflozin; wound healing

DOI:  https://doi.org/10.1161/ATVBAHA.126.324596
Nat Commun. 2026 Jun 23.

MYDGF promotes pathological and physiological retinal angiogenesis via the Gαi1/3-Gab1-Akt-mTOR signaling.

Ke-Ran Li, Ping-Ping Fu, Wen Bai, Chao-Wen Bai, Yitian Yang, Le Liu, Jin-Long Chai, Yujia Yao, Dan Huang, Zhi-Qing Zhang, Qin Jiang, Zhou-Rui Ma, Yu Feng, Jin Yao, Cong Cao.

Retinal neovascularization (RNV) is a potential vision-threatening process characterized by the abnormal growth of retinal vessels. Despite its clinical prevalence, the precise mechanisms governing RNV initiation and progression remain incompletely defined. Here we identify myeloid-derived growth factor (MYDGF) as a critical regulator of retinal vascular dynamics. Using single-cell RNA sequencing and human patient validation, we show that MYDGF is upregulated in retinal endothelial cells during proliferative diabetic retinopathy and mouse models of pathological neovascularization. In vitro, MYDGF promotes retinal endothelial cell proliferation, migration, and sprouting. In vivo, endothelial-specific MYDGF depletion inhibits both normal vascular development and pathological neovascularization in neonatal mice, and disrupting adult vascular homeostasis in male mice. MYDGF drives angiogenesis by activating the Akt-mTOR cascade through the Gαi1/3-Gab1 signaling complex; genetic depleting or mutation these components suppress MYDGF-induced Akt-mTOR activation and angiogenic responses. Together, MYDGF promotes retinal angiogenesis and maintains vascular homeostasis via the Gαi1/3-Gab1-Akt-mTOR signaling axis.

DOI: https://doi.org/10.1038/s41467-026-74780-9
Trends Pharmacol Sci. 2026 Jun 23. pii: S0165-6147(26)00139-2. [Epub ahead of print]

Targeting developmental reprogramming: hPSC insights for cancer interception.

Xiaohui Xu, Xiaolei Dong, Jinyu Li, Yifei Liu, Zheng Wang.

  Cancer is increasingly conceptualized as a disease of distorted human development, where oncogenic events trigger developmental reprogramming by subverting physiological lineage programs. Conventional cancer models often fail to capture this early transition, as they primarily reflect end-stage tumors or nonhuman biology. Human pluripotent stem cells (hPSCs) circumvent these limitations by enabling the reconstruction of oncogenic events within precisely defined human developmental trajectories. In this review, we examine emerging principles of lineage bias and differentiation arrest revealed by hPSC-derived models across brain, retinal, and myeloid malignancies, as well as hereditary cancer predispositions. Crucially, we discuss how these models reveal therapeutic windows linked to defined developmental states to reverse lineage hijacking, translating developmental insights into pharmacological strategies for early cancer interception.

Keywords:  cancer interception; developmental reprogramming; epigenetic alteration; human pluripotent stem cells; lineage specification; stage-specific pharmacology

DOI:  https://doi.org/10.1016/j.tips.2026.05.011
J Extracell Vesicles. 2026 Jun;15(6): e70328

Exosomal Oleic Acid Promotes Lymphangiogenesis and Nodal Metastasis in Cervical Cancer via the AKT/mTOR Pathway.

Jinqiu Li, Xiaojing Huang, Guzhalinuer Abulizi, Ayshamgul Hasim.

  Cervical cancer (CC) exhibits a pronounced tropism for regional lymphatic dissemination, a process driven by tumor-associated lymphangiogenesis. While metabolites within the metastatic niche are increasingly recognized as determinants of organotropic metastasis, the role of exosome-mediated metabolite transfer in tumor-lymphatic endothelial cell (LEC) crosstalk remains largely unexplored. Here, we demonstrate that oleic acid (OA) is significantly enriched in both CC lymph node metastases and the peritumoral lymphatic microenvironment. Exosomes derived from highly metastatic CC cells actively package OA in a manner dependent on stearoyl-CoA desaturase (SCD), the rate-limiting enzyme of de novo fatty acid synthesis. Upon internalization by LECs, exosomal OA triggers the AKT/mTOR signaling axis, eliciting robust LEC proliferation and endothelial-to-mesenchymal transition (EndMT), thereby fostering lymphangiogenesis and nodal colonization. Knockdown of SCD abolishes these pro-lymphangiogenic effects, a deficit fully reversed by the reconstitution of OA-loaded exosomes. In vivo, exosomes from SCD-silenced cells exhibit a severely compromised capacity to drive primary tumor growth, intratumoral lymphangiogenesis, and lymph node metastasis (LNM). Notably, free OA administration exerts substantially weaker effects than its exosomal counterpart, underscoring the superior efficiency of exosome-mediated metabolite trafficking. Clinically, FASN and SCD expression are significantly upregulated in lymph node-positive specimens and positively correlate with lymphatic vessel density and p-AKT levels. Furthermore, circulating exosomal OA levels are significantly elevated in patients with nodal involvement, suggesting its potential as a non-invasive diagnostic biomarker. Collectively, our findings establish a paradigm wherein tumor-derived exosomes function as specialized vehicles for intercellular OA transfer, activating the AKT/mTOR pathway to license lymphangiogenic reprogramming. This work identifies exosomal metabolite shuttling as a central node in tumor-lymphatic communication and proposes targeting OA synthesis or exosomal delivery as a promising therapeutic strategy against CC metastasis.

Keywords:  AKT/mTOR pathway; cervical cancer; exosomes; lymphangiogenesis; oleic acid

DOI:  https://doi.org/10.1002/jev2.70328