bims-lypmec 2026-10-18 papers

Front Endocrinol (Lausanne). 2026 ;17 1989060

Glycometabolic burden and myocardial involvement: a relational two-axis hypothesis.

Keywords: cardiac biomarkers; diabetic cardiomyopathy; diabetic myocardial disorder; heart failure; prediabetes

DOI: https://doi.org/10.3389/fendo.2026.1989060

Front Pharmacol. 2026 ;17 1911117

Targeting lysosomal ion channels to overcome cancer treatment resistance: emerging mechanisms and therapeutic opportunities.

Na Luo, Qiuxiang Wang, Jun Zhang, Zhiqin Deng.

Lysosomes are critical cellular organelles that not only regulate metabolic regulation but also play pivotal roles in cell death, signal transduction, and tumorigenesis. The various ion channels expressed on the lysosomal membrane are central to these physiological functions; they intricately maintain lysosomal pH homeostasis, calcium ion homeostasis, and membrane potential. Consequently, the dysregulation of these channels has emerged as a potential target of tumor cells, driving tumor cell proliferation, metastasis, apoptosis, and drug resistance. This review summarizes the structure and function of major lysosomal ion channels, emphasizing their central roles in regulating the tumor microenvironment, cell survival, and treatment resistance. Specifically, we highlight their involvement in mediating resistance to chemotherapy, radiotherapy, and immunotherapy, elucidating the associated molecular mechanisms. Furthermore, we explore the prospects and challenges of developing targeted therapeutic strategies towards these ion channels to overcome tumor drug resistance.

Keywords: drug resistance; immunotherapy resistance; ion channel; lysosome; radiotherapy resistance; tumor therapy

DOI: https://doi.org/10.3389/fphar.2026.1911117

Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2627551123

Membrane contact activation of Piezo2 drives lysosome-mitochondrion Ca2+ transfer and signaling in Trypanosoma cruzi.

Guozhong Huang, Roberto Docampo.

Calcium ion (Ca2+) transfer from other organelles is central to mitochondrial metabolism and cell survival, yet how mechanical forces regulate interorganelle communication remains unclear. Here we report a lysosome-to-mitochondrion pathway in Trypanosoma cruzi, the etiologic agent of Chagas disease, mediated by the mechano/osmosensitive channel TcPiezo2. Using ultrastructural, biochemical, and live-cell superresolution imaging, we define lysosome-mitochondrion contact sites (LMCs) that enable direct Ca2+ transfer. TcPiezo2 triggers Ca2+ release, which generates perilysosomal nanodomains that drives mitochondrial Ca2+ uptake via the voltage-dependent anion channel and the mitochondrial Ca2+ uniporter complex. Disruption of TcPiezo2-dependent Ca2+ transfer impairs mitochondrial metabolism, perturbs redox homeostasis, induces autophagy, and eventually leads to parasite death. These findings establish LMCs as a signaling platform that directly regulates interorganelle Ca2+ transfer and mitochondrial bioenergetics.

Keywords: Piezo channel; calcium; lysosomes; membrane contact sites; mitochondria

DOI: https://doi.org/10.1073/pnas.2627551123

Mol Cell. 2026 Oct 14. pii: S1097-2765(26)00667-2. [Epub ahead of print]

STING engages PKR to drive lysosomal cell death in lung ischemia-reperfusion injury.

Peigen Gao, Tao Wang, Yingjian Liu, Fenghui Zhuang, Chongwu Li, Guodong Wu, Yifang Dang, Huikang Xie, Chenyang Dai, Mengmeng Zhao, Deping Zhao, Xiangyang Wu, Chang Chen, Haipeng Liu, Junqi Wu.

Stimulator of interferon genes (STING) has been implicated in multiple forms of cell death. However, the effector kinases that couple STING to these death programs remain poorly defined. Here, we show that during lung ischemia-reperfusion injury, mitochondrial DNA release engages the cyclic GMP-AMP synthase (cGAS)-STING pathway to trigger lysosomal cell death (LCD) in mouse and rat models. In human lung epithelial cells, STING oligomerization at the endoplasmic reticulum drives autophosphorylation of double-stranded RNA-dependent protein kinase (PKR) at serine 33. This phosphorylation of PKR activates IκB kinase-NF-κB signaling independently of the canonical STING-TBK1 and PKR-eIF2α pathways. In turn, NF-κB induces LAMP3 transcription, promoting lysosomal membrane permeabilization and LCD. STING-PKR signaling is also observed in patient-derived lung epithelial cells and alveolar organoids. These findings identify PKR as a non-canonical STING effector and show that blockade of STING-PKR signaling attenuates epithelial LCD and lung injury.

Keywords: LAMP3; PKR; STING; lung ischemia-reperfusion injury; lysosomal cell death

DOI: https://doi.org/10.1016/j.molcel.2026.09.024

BMC Cardiovasc Disord. 2026 Sep 29. pii: 927. [Epub ahead of print]26(1):

Multi-omics profiling reveals coordinated metabolic and immuno-inflammatory remodeling in a high-fat diet and single-dose streptozotocin-induced mouse model of diabetic cardiomyopathy.

Feng Zhang, Chunbo Ai, Hao Zhang, Xiaoqiang Sun, Li Wang, Chao Li, Wei Cai, Xuemei Yin, Yanxin Wang, Yanwei Li, Chengzhi Lu, Zhuqing Li.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a major myocardial complication of type 2 diabetes and a contributor to heart failure. However, coordinated remodeling across the cardiac transcriptome, proteome and metabolome in DCM remains incompletely defined.
METHODS: Type 2 diabetes was induced in mice by a high-fat diet combined with single-dose streptozotocin. DCM was characterized by echocardiography, histology, transmission electron microscopy, and systemic metabolic and inflammatory assessments. Left ventricular myocardium underwent RNA sequencing, quantitative proteomics and untargeted metabolomics, followed by integrated pathway and network analyses. Selected pathways were further examined by biochemical assays, with additional evaluation of mitochondrial injury and cGAS-STING signaling.
RESULTS: Diabetic mice developed systolic and diastolic dysfunction with ventricular remodeling, interstitial fibrosis, mitochondrial ultrastructural damage, insulin resistance, and heightened systemic and myocardial inflammation. Transcriptomic and proteomic profiling revealed concordant suppression of sarcomeric organization, calcium handling, and mitochondrial oxidative metabolism, indicating downregulation of a contraction-calcium-mitochondrial energetics axis. Metabolomics showed reduced pyruvate-linked intermediates and enrichment of pentose phosphate, nucleotide and glutathione-related metabolites, consistent with diversion of central carbon flux from mitochondrial oxidation toward redox and biosynthetic programs. Across all three omics layers, phospholipid-choline metabolism emerged as a remodeled hub connecting central carbon pathways with complement, cell adhesion and inflammatory signaling. Increased cGAS-STING activity in DCM myocardium further linked mitochondrial injury to innate immune activation.
CONCLUSIONS: Integrated multi-omics analysis reveals coordinated remodeling across mitochondrial function, metabolism, inflammation, and fibrosis in experimental DCM. Alterations in phospholipid-choline metabolism, pentose phosphate and central carbon pathways, cGAS-STING signaling, and the contraction-calcium-mitochondrial module were concurrently observed and collectively characterize the molecular landscape of diabetic cardiomyopathy. These findings provide a framework for future mechanistic studies and may help identify candidate biomarkers and potential therapeutic pathways for further investigation.

Keywords: Diabetic cardiomyopathy; Mitochondrial dysfunction; Multi-omics integration; Phospholipid-choline metabolism; cGAS–STING pathway

DOI: https://doi.org/10.1186/s12872-026-06682-z