Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and amyotrophic lateral sclerosis, share common pathological features, including abnormal protein aggregation, chronic neuroinflammation and progressive neuronal loss. Ageing is the strongest risk factor, accompanied by a chronic, mild inflammatory state called ‘inflammaging,’ partly due to senescent cells producing senescence-associated secretory phenotype (SASP) factors. Innate immune DNA- and danger-sensing pathways, most notably the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasomes, convert cellular injury into chronic neuroinflammation. Here, we propose that protein pathology, SASP, and innate immune activation form a self-amplifying triangular circuit leading to age-related neurodegeneration. We present the cellular and molecular basis of each part and how microglia, astrocytes, oligodendrocyte precursor cells and neurons contribute. We outline treatment strategies, including senolytics, senomorphics, innate immune pathway inhibitors and metabolic restoration, and identify unresolved questions, including the reversibility of post-mitotic neuronal senescence, the relative contribution of each cell type and the translational challenge of interrupting the cycle. Collectively, the neuro-inflammaging triangle theory shifts focus from individual pathogenic entities to the self-amplifying circuit that sustains them, offering a unified mechanistic model to advance our understanding and treatment of age-related neurodegeneration. Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are marked by protein aggregates, cellular senescence and chronic inflammation. This study explores the interconnected roles of protein aggregation, senescence and ‘neuro-inflammagingʼ, a chronic inflammatory state activated through innate immune pathways, forming a self-amplifying circuit that exacerbates neurodegeneration. The authors review recent advances, highlighting how protein aggregates induce cellular senescence, which in turn activates immune pathways such as cGAS-STING and NLRP3 inflammasomes, perpetuating inflammation. They review single-cell and spatial transcriptomics data, highlighting key findings such as identifying senescent markers in various brain cells and the role of SASPs in spreading pathology. They also discuss cell-specific functions in the neuro-inflammaging circuit and propose therapeutic strategies targeting these processes, suggesting that disrupting this circuit could slow disease progression, and that future research should focus on cell-type specificity and therapeutic interventions aimed at multiple sites. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Bone metastasis of breast cancer is a multistep process involving detachment from the primary tumor, homing and adhesion to bone, clonal survival, and osteolysis, driven by dynamic interactions between tumor cells and the bone microenvironment. Although Runt-related transcription factor 2 (RUNX2) has been recognized as a downstream effector of SMADs in bone metastatic programs, our study has revealed that SMAD–RUNX2 complexes also regulate the intrinsic functions of SMADs, thereby acting as active amplifiers of TGFβ and BMP signaling. We further characterized the distinct roles of the SMAD1–RUNX2 and SMAD2/3–RUNX2 complexes across the bone metastatic cascade using cancer cells overexpressing either wild-type RUNX2 or RUNX2 variants in response to treatment with TGFβ and BMP. SMAD–RUNX2 complexes were found to play microenvironment-dependent roles during bone metastasis. The TGFβ-induced SMAD2/3–RUNX2 complex promoted osteotropic migration and secondary dissemination, whereas the BMP-activated SMAD1–RUNX2 complex increased cancer cell adhesion and survival in the bone microenvironment, with both complexes increasing osteolytic lesion formation. Mechanistically, the competitive binding of SMAD2/3 and SMAD1 to RUNX2 appeared to underlie the crosstalk between the TGFβ and BMP pathways. Together, these findings demonstrate a dynamic interplay among SMAD1, SMAD2/3, and RUNX2 that integrates TGFβ and BMP signaling during bone metastasis, highlighting the potential for developing context-dependent therapeutic strategies. Bone metastasis is a significant complication of breast cancer, severely impacting patients' quality of life and survival. This study explores the roles of SMAD1–RUNX2 and SMAD2/3–RUNX2 complexes in breast cancer bone metastasis. Researchers used breast cancer cells with wild-type or mutated RUNX2 to analyze the effects of these complexes under TGFβ and BMP treatments. They found that SMAD2/3–RUNX2 promotes cancer cell migration to bone, while SMAD1–RUNX2 enhances cell adhesion to bone. These complexes differentially regulate gene expression related to metastasis, with SMAD2/3–RUNX2 facilitating dissemination and SMAD1–RUNX2 supporting bone colonization. The findings highlight the role of RUNX2 as a transcriptional amplifier in TGFβ and BMP signaling, suggesting potential therapeutic targets for managing bone metastasis. Future research could focus on disrupting SMAD–RUNX2 interactions to develop treatments for bone metastasis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Engineering cell identity has transitioned from descriptive developmental biology into a predictable, quantitative discipline. Central to this transition is the discovery that single transcription factors (TFs) can act as master regulators, capable of bypassing hierarchical developmental constraints to directly reprogram cell fate. Although early studies relied on candidate-based approaches, recent technological advances in high-throughput methods and single-cell multi-omics have revolutionized the field. In this Review, we focus on the emergence of large-scale single-TF overexpression screens as a discovery engine for lineage regulators. We discuss how systematic overexpression screens, particularly in pluripotent stem cell systems, have enabled the identification of single TFs with cell-fate reprogramming potential. We examine the shift from bulk transcriptomics to single-cell trajectory inference, which reveals the inherent heterogeneity, rapid kinetics, and stochastic nature of fate reprogramming. Furthermore, we interrogate the mechanistic features that need to be considered during fate transitions, such as pioneer factor activity, chromatin competence, and dosage-dependent lineage bifurcations. By integrating large-scale TF overexpression data with multi-omic readouts, we discuss principles for cell-fate engineering and define successful conversion through transcriptional stability, epigenetic memory, and functional maturity. This systematic perspective provides a roadmap for the precise generation of therapeutic cell types in regenerative medicine. Cellular identity is shaped by transcription factors (TFs) that regulate gene expression through interactions with DNA elements. Recent studies have expanded the list of TFs capable of reprogramming cell fates, yet only a few have been thoroughly validated. This Review highlights the use of pluripotent stem cells as a platform to systematically compare TF activity across developmental paths, focussing on single-TF perturbation to identify lineage determinants. High-throughput screening and single-cell transcriptomics reveal that TFs can induce lineage-specific programs, but outcomes are context-dependent. Notably, TF dosage and chromatin accessibility have crucial roles in determining cell fate. This Review emphasizes the need for rigorous functional validation to bridge the gap between transcriptomic resemblance and physiological function. Future directions include integrating high-throughput data with computational models to enhance cell-fate engineering, with potential applications in regenerative medicine and disease modeling. "This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author."
Hepatic ischemia–reperfusion injury (HIRI), a major complication following liver surgery, involves neutrophil infiltration and hepatocyte apoptosis that contribute to graft failure and multiorgan injury; however, the role of neutrophil–hepatocyte crosstalk remains unclear. Through proteomic profiling, leucine-rich α-2 glycoprotein 1 (LRG1) was identified as a markedly upregulated protein in mouse HIRI models, a finding corroborated by elevated plasma LRG1 levels in patients who underwent hepatectomy. In mice, hepatocyte-derived LRG1 precedes neutrophil extracellular trap (NET) formation and hepatocyte apoptosis. Hepatocyte-specific Lrg1 knockout attenuated liver injury, inflammation, neutrophil infiltration, NET formation, and apoptosis. Mechanistically, LRG1 secreted from hepatocytes binds to TGFβ receptor 1 (TGFβR1) on neutrophils, activating SMAD3 to promote Pad4 transcription and NETosis. Subsequent NETs initiate AIM2-dependent hepatocyte apoptosis and propagate injury to the kidneys, resulting in AIM2-mediated renal tubular damage—effects ameliorated by DNase I treatment or AIM2 deficiency. Importantly, molecular docking and surface plasmon resonance analyses identified dothiortone, a mangrove-derived polyketide, as a high-affinity LRG1 inhibitor. Dothiortone effectively suppressed NETosis and mitigated HIRI-induced hepatic and renal injury in vivo. These findings demonstrate that hepatocyte-derived LRG1 exacerbates HIRI and remote kidney injury via the TGFβR1–SMAD3–PAD4 axis and NET-driven AIM2-dependent apoptosis, highlighting LRG1 inhibition by dothiortone as a promising therapeutic strategy for HIRI and its systemic complications. Hepatic ischemia–reperfusion injury (HIRI) poses significant challenges in liver surgery and transplantation owing to oxidative stress and inflammation, leading to liver and remote organ damage, such as acute kidney injury. This study identifies leucine-rich α-2 glycoprotein 1 (LRG1) as a key player in exacerbating HIRI by promoting neutrophil extracellular trap (NET) formation, which triggers apoptosis in liver cells and contributes to kidney damage. Researchers used hepatocyte-specific Lrg1-knockout mice and found that LRG1 deficiency reduced liver injury and apoptosis, highlighting the role of LRG1 in neutrophil recruitment and NET formation. The study also demonstrated that NET-derived DNA activates the AIM2 pathway, leading to apoptosis. Furthermore, the study explored dothiortone, which inhibits LRG1, reducing NET formation and subsequent liver and kidney damage. These findings suggest targeting the LRG1–NET axis as a promising therapeutic approach for HIRI. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
Our findings in excitable cells support the recent work of Kim et al. (Exp Mol Med 57:2717–2728, 2025), which describes a direct interaction between ion channels and G proteins. We identified a direct interaction between muscarinic receptors, voltage-dependent sodium channels (VDSC), and Go proteins in mammalian excitable cells. Their interaction was dependent on the opening of the VDSC pore, and it implicated modifications in the VDSC transmembrane S6 segments that orchestrate the channel pore opening in coordination with the VDSC voltage sensors.
