bims-imesem 2026-06-21 papers

bims-imesem

Biomed News

on Immunemetabolism

Issue of 2026–06–21
seven papers selected by
Akshara Kulkarni , University of Cambridge

A cyclin-polarity feedback network ensures healthy cell proliferation.
Mitochondrial dynamics and T cells immunity in cancer.
The CFIm25/FDPs axis orchestrates protective mitophagy in macrophages to attenuate myocardial infarction.
β-catenin-driven innate and metabolic reprograming in macrophages fuel T-cell-dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention.
Mitochondrial translocation of p210 BCR-ABL rewires downstream signaling by selectively suppressing ERK activation.
CD8 T lymphocytes deploy embryonic cell cycle control mechanisms for rapid cell proliferation.
Palbociclib targets β-catenin for degradation and synergizes with KRAS or ERK5 inhibition in colorectal cancer preclinical models.

Nat Commun. 2026 Jun 19.

A cyclin-polarity feedback network ensures healthy cell proliferation.

Landry Peyran, Charles Lefranc, Steven P Gygi, Anne Royou, Derek McCusker.

Healthy proliferation requires the coordination of cell cycle progression with cell polarity. In budding yeast, polarity is established when G1-cyclin-Cdc28Cdk1 triggers Cdc42 activation to generate a cell pole that is used as an axis for growth and division. While polarity defects delay the cell cycle temporally, permitting error correction, it is unknown if Cdc28Cdk1 directly rectifies errant polarity. Here, we identify an adaptive response where G1-cyclin-Cdc28Cdk1 participates in error correction via the augmentation of its kinase activity towards substrates that activate Cdc42. The response involves temporal and spatial cell cycle reconfiguration via extended G1 cyclin expression, nucleocytoplasmic rerouting and signaling. However, this strategy has a cost: if the defect is irreparable, high G1-cyclin levels enforce inexorable cell cycle commitment in the absence of a daughter cell, generating multinucleate cells. G1-cyclins therefore not only trigger G1 events, but also monitor their execution, employing feedback to coordinate polarity with cell cycle progression.

DOI: https://doi.org/10.1038/s41467-026-74596-7
Biochem Biophys Rep. 2026 Sep;47 102659

Mitochondrial dynamics and T cells immunity in cancer.

Xiaomei Li, Minghui Zhang, Yan Wang, Muhan Li, Tianzhen Wang, Xi Liu.

  Mitochondria are dynamic organelles that continuously adapt their number, morphology, and subcellular distribution in response to physiological and pathological stimuli. This plasticity is governed by a set of highly coordinated processes-collectively termed mitochondrial dynamics-including fusion, fission, mitophagy, and transport. Mitochondrial dynamics are essential for regulating cellular energy metabolism, proliferation, differentiation, and migration. Accumulating evidence highlights the critical role of mitochondrial dynamics in anti-tumor immunity, while their dysregulation contributes to immune evasion in cancer. In this review, we systematically outline how mitochondrial dynamics regulate the key stages of the T-cell immune response-from activation and differentiation to tumor infiltration, and finally to effector-mediated recognition and elimination of cancer cells-and elucidate the multifaceted mechanisms by which tumor cells suppress T-cell immunity through the regulation of mitochondrial dynamics. We aim to provide readers with an integrated conceptual framework, point toward future directions for translating fundamental insights into novel "metabolism-immunity" combination therapies, and thereby offer a theoretical foundation and strategic perspective for overcoming current bottlenecks in tumor immunotherapy.

Keywords:  Cancer; Metabolic reprogramming; Mitochondria; Mitochondrial dynamics; T cell immunity

DOI:  https://doi.org/10.1016/j.bbrep.2026.102659
Biochim Biophys Acta Mol Basis Dis. 2026 Jun 18. pii: S0925-4439(26)00190-0. [Epub ahead of print] 168327

The CFIm25/FDPs axis orchestrates protective mitophagy in macrophages to attenuate myocardial infarction.

Ye Zhou, Yi Li, Meng Liu, Mingyue Chen, Hui Guo, Jianzhi Qi, Shihao Han, Ting Yu, Ying Cao, Yifei Chen, Mei Hong.

  Alternative cleavage and polyadenylation (APA) is a major post-transcriptional regulatory mechanism that is frequently dysregulated following myocardial infarction (MI). To investigate its role in post-infarction remodeling, we focused on the APA factor cleavage factor Im 25 kDa subunit (CFIm25). We identified macrophage CFIm25 as a pathological regulator of MI and explored its association with mitochondrial quality control. CFIm25 expression was markedly reduced in macrophages during the early stage of MI. Myeloid-specific CFIm25 knockdown significantly reduced infarct size, attenuated cardiac fibrosis, and improved cardiac function after MI. In vitro, CFIm25 deficiency suppressed pro-inflammatory responses and enhanced mitophagic flux, whereas CFIm25 overexpression abolished these protective effects. Transcriptomic analysis identified farnesyl diphosphate synthase (FDPS) as a key downstream effector associated with CFIm25 deficiency. Although FDPS was not established as a direct APA target, our data support its functional role in mediating the downstream effects of CFIm25 loss. Quantitative proteomic profiling revealed significant enrichment of mitochondria-related pathways, indicating extensive mitochondrial remodeling following CFIm25 depletion. Pharmacological inhibition of FDPS using ibandronate attenuated PINK1/Parkin pathway activation, reduced LC3-II accumulation, and suppressed mitophagy, demonstrating that FDPS is functionally required for CFIm25 deficiency-induced mitophagic responses. Collectively, these findings support a model in which CFIm25 deficiency promotes FDPS-dependent activation of PINK1/Parkin-mediated mitophagy, thereby enhancing mitochondrial quality control and limiting inflammation. This study identifies a previously unrecognized CFIm25/FDPS signaling axis regulating macrophage mitophagy following MI and highlights its potential therapeutic relevance in ischemic heart injury.

Keywords:  Alternative cleavage; Inflammation; Macrophagy; Mitophagy; Myocardial infarction; Polyadenylation

DOI:  https://doi.org/10.1016/j.bbadis.2026.168327
Cell Death Dis. 2026 Jun 13. pii: 568. [Epub ahead of print]17(1):

β-catenin-driven innate and metabolic reprograming in macrophages fuel T-cell-dependent inflammation in Toxoplasma gondii infection: implications for therapeutic intervention.

Geetika Kumari, Amit Kumar, Rasmiranjan Muduli, Mayami Das, Prithwik Bhowmik, Biplab Singha, Ankita Namdeo, Criss Dcosta, Neerja Wadhwa, Jaswinder Singh Maras, Rakesh Kundu, Nishith Gupta, Ruchi Anand, Dhanasekaran Shanmugam, Tanmay Majumdar.

Toxoplasma gondii activates innate immunity via TLR11/12 in mice, but the lack of functional human counterparts leaves a gap in understanding parasite sensing in humans. Here, we bridge this gap by uncovering a host-intrinsic sensing mechanism, wherein β-catenin signaling mediates immune recognition of T. gondii. Notably, this parasite hijacks the PI3K-AKT-β-catenin pathway in macrophages to promote its replication. While β-catenin ablation, either genetically or pharmacologically (XAV939), disavows this process, thereby inhibiting replication. Phospho-β-catenin-TCF4 drives IRF4 transcription, followed by phosphorylation of IRF4, which regulates CYBB transcription. Augmented CYBB enhances mitochondrial-ROS and triggers mitophagy via PINK1/PARKIN, whereas ablation of β-catenin preserves mitochondrial fitness, thereby impeding parasite growth. Enhanced ROS can oxidize host mitochondrial DNA, which then functions as a host-associated molecular pattern (HAMP). This activates the cytosolic pathogen recognition receptor (PRR) AIM2, triggering the AIM2-NLRP3-ASC-caspase-1-IL-1β inflammasome cascade. This cascade leads to gasdermin-D-mediated pyroptosis, a process that critically depends on the phosphorylation of β-catenin. T. gondii's ASP5 protease plays an essential role in the phosphorylation of β-catenin-mediated inflammasome activation. Metabolically, β-catenin-dependent enhanced ROS stabilized HIF-1α, which stimulates the HKII-LDH-A axis, promoting the Warburg effect, histone acetylation and pro-inflammatory M1-macrophage polarization (IL-12/IL-6/IL-23/TNF-α). β-catenin ablation shifts metabolism to oxidative-phosphorylation, fostering M2-phenotype (IL-2/IL-10/TGF-β) that abrogates parasites survival. β-catenin also strengthens MHC-TCR avidity, driving Th1/Tc1, Th9/Tc9, and Th17/Tc17 paradigm, whereas β-catenin inhibition promotes anti-inflammatory Th2/Tc2/Threg/Tcreg differentiation. Additionally, macrophage intrinsic β-catenin dictates metabolic divergence in both CD4⁺ and CD8⁺T-cells. Notably, β-catenin-deletion in macrophages protects mice (β-catΔMΦ) against infection, highlighting that XAV939 has therapeutic potential against toxoplasmosis.

DOI: https://doi.org/10.1038/s41419-026-08953-1
Biochem Biophys Res Commun. 2026 Jun 17. pii: S0006-291X(26)00932-0. [Epub ahead of print]829 154168

Mitochondrial translocation of p210 BCR-ABL rewires downstream signaling by selectively suppressing ERK activation.

Yuta Okuda, Miho Watanabe-Takahashi, Kiyotaka Nishikawa.

  Chronic myeloid leukemia (CML) is a myeloproliferative disorder driven by the fusion protein p210 BCR-ABL. In addition to activating canonical cytosolic signaling pathways, p210 BCR-ABL has been shown to translocate to the mitochondria upon mitochondrial damage through the interaction between its pleckstrin homology domain and cardiolipin, a mitochondria-specific phospholipid. We recently demonstrated that a fraction of p210 BCR-ABL localizes to the mitochondria in CML cells and promotes cell survival through mitochondria-associated signaling. However, whether mitochondria translocation of p210 BCR-ABL affects the major downstream signaling pathways activated by p210 BCR-ABL remains unclear. Here, we investigated the effects of mitochondrial translocation of p210-BCR-ABL on the JAK2/STAT5-, PI3K/AKT-, and RAS/MAPK-pathways using HEK293T cells expressing p210 BCR-ABL. Carbonyl cyanide m-chlorophenylhydrazone (CCCP), which induces mitochondrial damage and subsequent mitochondrial translocation of p210 BCR-ABL, markedly reduced ERK activation, whereas STAT5 and AKT activation were largely unaffected. Consistently, phosphorylation of SHC1, an adaptor protein directly phosphorylated by p210 BCR-ABL and required to ERK activation, was also suppressed by CCCP treatment. In contrast, CCCP did not affect EGF-induced ERK activation, indicating that the observed effect was specific for p210 BCR-ABL signaling. Moreover, N-acetylcysteine inhibited CCCP-induced reactive oxygen species production, prevented mitochondrial translocation of p210 BCR-ABL, and fully restored ERK-activation. These findings suggest that intercellular relocation of p210 BCR-ABL dynamically rewires downstream signaling networks, potentially optimizing the signaling balance required for CML cell survival and proliferation.

Keywords:  Cardiolipin; ERK; Mitochondria; ROS; SHC1; p210 BCR-ABL

DOI:  https://doi.org/10.1016/j.bbrc.2026.154168
EMBO Rep. 2026 Jun 18.

CD8 T lymphocytes deploy embryonic cell cycle control mechanisms for rapid cell proliferation.

David A Lewis, Ananya Kar, Alice Savage, Van Kelly, David Wright, Devin Tan, Mary Tozer, Christina Rollings, Doreen A Cantrell, Rose Zamoyska, Tony Ly.

Rapid proliferation of CD8 T cells is crucial for adaptive immunity against viral infection. CD8 T cells can complete division cycles in less than 6 h, representing a physiological extreme for somatic mammalian cells. Embryonic stem cells utilize specialized cell cycle control mechanisms, including subdued periodic expression, for rapid cell division cycles. CD8 T cell cycle control remains poorly understood. Here, we test whether CD8 T cells utilize embryonic mechanisms to promote rapid cell cycles. We comprehensively measure protein abundances in G1, S, and G2&M phases in three murine cell types: CD8 T cells, embryonic stem cells, and fibroblasts. We discover striking similarities between mESC and CD8 T cells. We demonstrate that CD8 T cells express Cyclin E1 and Emi1/Fbxo5 at high levels to promote S-phase entry. Interestingly, CD8 T cells and mESCs differ in the frequency of G2&M phase cells, the abundance of DNA replication origin licensing and initiation factors, and the abundance of APC/C substrates. Thus, somatic T cells have both unique and shared cell cycle control mechanisms to promote rapid cell cycles.

DOI: https://doi.org/10.1038/s44319-026-00830-4
J Transl Med. 2026 Jun 19.

Palbociclib targets β-catenin for degradation and synergizes with KRAS or ERK5 inhibition in colorectal cancer preclinical models.

Matteo Villa, Federica Malighetti, Alberto Maria Villa, Nicoletta Cordani, Andrea Aroldi, Alfonso Zambon, Daniele Ramazzotti, Luca Mologni.

   BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, largely driven by aberrant activation of the WNT/β-catenin and RAS pathways. Despite recent therapeutic advances, effective strategies to target these oncogenic signals remain limited.
METHODS: A multi-step chemical library screen was performed to identify compounds capable of suppressing β-catenin and RAS signaling. Drug mechanisms and combination effects were investigated through functional assays, in vitro and in vivo experiments, and transcriptomic profiling. Survival analysis of the Sidra-LUMC AC-ICAM CRC cohort (n = 303) was conducted to evaluate the prognostic significance of candidate target genes.
RESULTS: We identified the CDK4/6 inhibitor palbociclib as an unexpected suppressor of β-catenin signaling. Uniquely, palbociclib promoted GSK3β-mediated β-catenin degradation by dampening AKT activity, revealing a previously unrecognized mechanism of action and broadening its role beyond canonical cell-cycle inhibition. Building on this mechanism, we found that combining palbociclib with the KRASG12D-specific inhibitor MRTX1133 elicited potent and selective anti-tumor effects in vitro and in vivo. Parallel screening also revealed the ERK5 inhibitor ERK5-IN-1 as a promising combination partner: co-administration with palbociclib strongly suppressed proliferation across multiple CRC models, showed minimal toxicity in normal cells, and produced durable tumor control in vivo. Transcriptomic profiling indicated that both combinations converge on a common program of cancer cell-state reprogramming, characterized by suppression of proliferative drivers and remodeling of metabolic and mitochondrial pathways. Underscoring the clinical relevance of our findings, survival analysis of the Sidra-LUMC AC-ICAM CRC cohort (n = 303) revealed that ERK5 target genes CREB5 and NUPR1, identified in our dataset, were consistently linked to poor prognosis, thereby connecting this signaling axis to unfavorable patient outcomes.
CONCLUSIONS: Together, these findings position palbociclib as a versatile therapeutic backbone in CRC. By simultaneously targeting cell cycle and oncogenic signaling networks, palbociclib-based combinations induce synergistic and durable responses, offering a compelling rationale for tailored therapeutic strategies in molecularly defined CRC.

Keywords:  Colorectal cancer; ERK5; KRAS; Palbociclib; WNT/β-catenin signaling

DOI:  https://doi.org/10.1186/s12967-026-08420-7