Endothelial dysfunction is a hallmark of pathological angiogenesis and associated with erythrocyte extravasation and lysis. Whether mediators released from lysed erythrocytes instruct endothelial cells (ECs) for new vessel formation is unknown. Here, we show that the membrane fraction of lysed erythrocytes activates inflammatory endothelial gene transcription and metabolically reprograms ECs to promote angiogenic sprout formation. Alterations in endothelial glucose metabolism occurred downstream of NFκB p65 activation by extracellular ATP via fast-acting endothelial P2X7 receptors and also involved ATP-mediated adenylyl cyclase activation and cyclic AMP generation via P2RY11. Overexpression and acetylation of histone 3 at lysine 27 of NR4A1 was identified as anti-inflammatory control mechanism and angio-metabolic switch activating VEGF, PFKFB3 and other AP-1 dependent gene transcription programs. The angiogenic potential of lysed erythrocyte membranes from patients with peripheral artery disease was impaired and could be restored by inhibiting endothelial phosphodiesterase 4 to prevent endothelial cAMP degradation. Our findings uncover that erythrolysis metabolically primes ECs for angiogenesis and that targeting endothelial cAMP generation may be a promising strategy to restore endothelial angiogenic functions.
© 2026. The Author(s).

Glucagon-like peptide-1 (GLP-1) is a key incretin hormone rapidly degraded by circulating proteases such as DPP-4. The metabolism of GLP-1 by other proteases, particularly tissue-resident proteases, remains largely unexplored. Here, we identify insulin-degrading enzyme (IDE) as a previously unknown GLP-1-degrading protease with two cleavage sites. We show that IDE-mediated degradation of GLP-1, but not insulin, represents a major mechanism regulating glucose control. To resist IDE, we engineered GLP-1 and Semaglutide with D-amino acid substitutions at these sites. These peptides exhibit enhanced stability in plasma, liver and intestinal secretomes, peritoneal fluid, and central nervous system (CNS). D-Ser18-Semaglutide shows prolonged plasma retention and sustained glucose-lowering effects in mice. Moreover, IDE knockdown and intracerebral injection of D-Ser18-Semaglutide confirm IDE's physiological role in GLP-1 degradation, particularly in the CNS. These findings reveal a previously unidentified regulatory mechanism of GLP-1 metabolism and provide a strategy for designing long-acting agonists with improved metabolic and CNS therapeutic potential.

Achieving cell-selective targeted protein degradation remains a major challenge for translating proteolysis-targeting chimeras (PROTACs) into therapeutics. Although pancreatic β-cells are well vascularised and readily accessible to circulating peptides, selective receptor-mediated drug delivery remains challenging. Here, we exploit the glucagon-like peptide-1 receptor (GLP-1R) as a β-cell-specific entry route and report, for the first time, a multicomponent stapled glucagon-like peptide-1 (GLP-1) analogue constructed by tryptophan-mediated multicomponent Petasis reaction (TMPR). This modular stapling strategy affords a conformationally stabilised GLP-1 peptide bearing a chemically orthogonal handle for late-stage conjugation, displaying markedly enhanced α-helicity and improved receptor potency, compared with the wild-type peptide. Linking this improved analogue to a bromodomain-containing protein 4 (BRD4)-directed degrader furnishes the first GLP-1-guided PROTAC, which retains GLP-1R agonism and induces selective BRD4 degradation in GLP-1R-positive cells, consistent with receptor-guided uptake and intracellular activation of the degrader payload. Together, these results provide strong proof-of-concept evidence that a TMPR-stapled GLP-1 peptide can serve as a β-cell-directed delivery platform for receptor-defined protein degradation.
© 2026 The Author(s). Angewandte Chemie International Edition published by Wiley‐VCH GmbH.

Coronin proteins are present in all known non-plant eukaryotes, and are involved in key biological processes including cytoskeletal dynamics and the regulation of cell population sizes in amoeba and mammals. How, exactly, coronin proteins exert their function is debated. On the one hand, coronins are widely considered as F-actin-binding and regulatory proteins. On the other hand, coronin proteins were also shown to act as regulators of cAMP/Ca2+ signaling. Here, we demonstrate that endogenously expressed mammalian coronin 1, 2 and 3 did not depend on F-actin for their subcellular localization and did not impact actin-related processes that were previously reported to be coronin-dependent. We also show that the fusion of GFP or FLAG-tags to coronin proteins resulted in their increased colocalization with actin and phenocopied loss-of-function mutation in mice. Together these results suggest that inclusion of tags on coronin proteins causes increased colocalization with F-actin and can disrupt their in vivo function. Furthermore, we show that the ubiquitously expressed coronin 2 and coronin 3 regulated cAMP production regardless of the presence of F-actin. The analysis presented here may contribute to a re-evaluation of the function of coronin proteins in signaling, independently of actin modulation.
Copyright: © 2026 Gvozdenica Šipić et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Naturally occurring loss-of-function variants in human genes enable drug target discovery because they mimic pharmacological inhibition of proteins. However, the study of these genetic variants is constrained by their rarity. Sequencing of diverse populations, particularly those enriched in familial relatedness, has been postulated to promote discovery of rare genetic variants1-3. Here we present the Pakistan Genome Resource, a South Asian biobank with high familial relatedness comprising 173,303 participants, who collectively carry naturally occurring homozygous loss-of-function variants in 6,476 genes. We describe the genetic architecture of this population, associations between genes and biomarkers, the distribution of loss-of-function variants across molecular pathways, and recall-by-genotype studies of therapeutically relevant genes. The Pakistan Genome Resource expands the catalogue of human genetic variants, provides a comprehensive genetic reference resource for the Pakistani population, and demonstrates the value of studying diverse cohorts to advance human health.
© 2026. The Author(s).