bims-miptne 2026-07-12 papers

Nat Commun. 2026 Jul 10.

Molecular mechanisms of mitochondrial Ca2+ exchanger NCLX.

Li Zhang, Yan Han, Weizhong Zeng, Jing Xue, Yan Wang, Youxing Jiang.

Mitochondrial Ca²⁺ homeostasis is maintained through coordinated influx and efflux processes, with NCLX long recognized as the primary Ca²⁺ extruder operating via Na⁺/Ca²⁺ exchange. Here, we report cryo-EM structures of rat NCLX in cytosolic-facing occluded and open states. The central transmembrane (TM) domain of NCLX comprises ten helices arranged in two inverted, structurally similar halves, with two α-repeats forming a central ion-binding pocket. Peripheral TMs 1 and 6 are loosely associated with the core and likely mediate alternative access to this site. These structural features closely resemble those of NCXs, indicating a conserved ion exchange mechanism. While NCLX retains the canonical Ca²⁺-binding site, it lacks several key Na⁺-binding residues found in NCXs, suggesting broader ion selectivity. Consistently, cell-based Ca²⁺ uptake assays show that NCLX mediates Ca²⁺ exchange using Na⁺, K⁺, Li⁺, and potentially protons as counterions. Based on the structural symmetry of NCLX and its bidirectional exchange capability, we propose a matrix-facing model and an alternating-access mechanism in which TMs 1 and 6 undergo sliding motions to enable ion exchange between cytosolic and matrix sides, analogous to NCX. These findings provide a structural and mechanistic framework for understanding NCLX-mediated Ca²⁺ transport in mitochondria.

DOI: https://doi.org/10.1038/s41467-026-75483-x

J Med Chem. 2026 Jul 05.

Discovery of SD-2301 as a Highly Potent and Selective PROTAC STAT3 Degrader Capable of Achieving Complete Tumor Regression with Single Administration.

Ranjan Kumar Acharyya, Longchuan Bai, Haibin Zhou, Dimin Wu, Mi Wang, Hoda Metwally, Donna McEachern, Meilin Wang, Bo Wen, Duxin Sun, Shaomeng Wang.

STAT3 is a promising therapeutic target for human cancers and other diseases. Herein, we report our development of novel STAT3 proteolysis-targeting chimera degraders using high-affinity STAT3 and Von Hippel-Lindau 1 ligands, which led to the discovery of SD-2301 as a highly potent, selective, and efficacious STAT3 degrader. SD-2301 achieved DC50 = 4 nM and Dmax of >95% and is >100 times more potent than SD-36 and SD-91. SD-2301 is highly selective for inducing STAT3 degradation over other Signal Transducer and Activator of Transcription members. SD-2301 inhibited cell growth with IC50 = 5-11 nM in the SU-DHL-1 and SUP-M2 lymphoma cell lines. SD-2301 displayed an excellent pharmacokinetic profile in mice and achieved rapid and persistent depletion of STAT3 protein in native and xenograft tumor tissues in mice. SD-2301 was capable of achieving complete and long-lasting tumor regression in vivo and is a promising STAT3 degrader for the treatment of human cancers and other human diseases.

DOI: https://doi.org/10.1021/acs.jmedchem.6c00743

Sci Adv. 2026 Jul 10. 12(28): eaeb2695

The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.

Trametinib (Trm) is a highly selective mitogen-activated protein kinase kinase (MEK) inhibitor that potently and persistently abrogates extracellular signal-regulated kinase 1/2 activation. Trm initially was used to treat BRAF Val600→Glu (V600E)-mutated melanoma, but its Food and Drug Administration-approved indications are expanding rapidly. Trm generally is well tolerated, but it can cause dose-limiting cardiomyopathy and heart failure. Here, we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some cancer cell types. In vivo, Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High-resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part, through blunted activity of electron transport system complexes. Trm-mediated mitochondrial injury led to the release of mitochondrial damage-associated molecular patterns including mitochondrial DNA in both mice and humans, triggering activation of canonical innate immune pathways including cGAS-STING. In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations, but this lesion was reversed by expression of a phosphomimetic signal transducer and activator of transcription 3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all cancer cell lines, identifying a previously unrecognized effect that could contribute to Trm's anticancer efficacy.

DOI: https://doi.org/10.1126/sciadv.aeb2695

Nature. 2026 Jul 08.

Aneuploidy selects for the acquisition of driver genes in breast cancer.

Chromosome instability is highly prevalent in cancer and drives large-scale chromosomal imbalances, known as aneuploidies1-4. How aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. Here we established a CRISPR knockout- and activation-linked assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immunocompetent mouse models of cancer. We developed a compendium of the ten most frequent human chromosome-arm-level alterations in basal-like breast cancer (BLBC), a disease type that is driven by large copy-number alterations (CNAs)5-8. Using CRISPR-KOALA, we screened the mouse orthologues of 3,752 genes on these arms and identified 90 cancer driver genes, the function of the vast majority of which is unknown. These genes drive distinct signalling pathways including MAPK, HIPPO and WNT, reflecting the high degree of BLBC heterogeneity. Manipulating the identified cancer driver genes overcomes the need for CNAs in Trp53-mutant BLBC mouse models. Mechanistically, we identify that PLGRKT is a potent oncogene that lies on chromosome 9p and show that its tumour-promoting activity is associated with highly stress-resistant mitochondria and an increased ability to detoxify reactive oxygen species. Together, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogeneous biological processes.

DOI: https://doi.org/10.1038/s41586-026-10752-9

Nature. 2026 Jul 08.

Diet-microbiome synergy underlies obesity-associated immunotherapy efficacy.

Lysanne Desharnais, Anikka Swaby, Meriem Messaoudene, Samuel Doré, Miranda W Yu, Benoit Fiset, Valérie Breton, Mayra Ponce, Yongjia Hu, Liam Wilson, Mark Sorin, Ye Wang, Ken Dewar, Michael Pollak, Arielle Elkrief, Bertrand Routy, Logan A Walsh, Daniela F Quail.

Physiological host factors, such as the gut microbiome and obesity, independently influence anti-tumour immunity and responses to immune checkpoint inhibitors (ICIs)1, with high body mass index (BMI) having an unexpected link with greater ICI efficacy2-6. However, how these factors interact across diverse dietary contexts remains unclear. Here, using 12 mouse diet models that reflect a spectrum of obesity biology, we characterize diet-driven metabolic, immune and gut microbiota features associated with ICI sensitivity. We find that obesity-associated ICI responses are poorly correlated with metabolic dysfunction and are instead dependent on the diet-gut axis. Obesogenic diets promote a robust and persistent gut microbial ecosystem that is capable of restoring ICI sensitivity following a short-term diet switch or fecal microbiota transplants (FMTs) from non-responder models. Monocolonization of germ-free mice with favourable bacteria such as Lactobacillus johnsonii, together with an obesogenic diet, synergistically promotes tumour regression through an enrichment of microbiota-derived aromatic amino acid metabolites. Moreover, human-to-mouse FMT from donors with a high BMI enhanced ICI efficacy compared with donors with a normal BMI, and an obesogenic diet restored sensitivity following FMT from a non-responder patient. Our study provides insight on epidemiological associations between BMI and ICI efficacy, and suggests that immunomodulatory synergy between diet and the gut microbiota could be leveraged to improve ICI outcomes and FMT interventions.

DOI: https://doi.org/10.1038/s41586-026-10750-x