While recent studies have established links between metabolic reprogramming and inflammatory senescence, the specific metabolic drivers in vascular aging remain incompletely defined. Here, we systematically characterized senescent phenotypes and targeted metabolomic profiles in primary aging endothelial cells, identifying a pyruvate dehydrogenase E1 component subunit alpha (PDHA1)-dependent metabolic shift as a hallmark of cellular senescence. Using a D-galactose-induced senescence model, we demonstrated that endothelial-specific Pdha1 knockdown alleviated pulmonary vascular endothelial senescence and associated functional decline. Further investigation revealed that PDHA1 hyperactivation disrupts mitochondrial homeostasis, leading to excessive mitochondrial reactive oxygen species production, oxidative mitochondrial DNA damage, and subsequent cytosolic mitochondrial DNA release, thereby triggering cyclic GMP-AMP synthase-mediated senescence. Mechanistically, decreased lactylation of PDHA1 at lysine 336 potentiated its activity and promoted dephosphorylation at serine 293. This posttranslational cross talk enhanced PDHA1 activation and drove a prosenescent metabolic shift. Together, our results elucidate that a previously unrecognized PDHA1 hyperactivation promotes endothelial senescence.

Photocatalytic biomass refining offers a promising strategy for the sustainable co-production of high-value chemicals and clean fuels. Herein, a coral-like bifunctional g-C₃N₄/Mn_0.7Cd_0.3S S-scheme heterojunction (CNMCS) was rationally constructed for simultaneous xylan photoreforming and hydrogen evolution. X-ray diffraction and transmission electron microscopy analyses confirm the formation of an interconnected hierarchical structure with intimate interfacial contact between g-C₃N₄ nanotubes and Mn_0.7Cd_0.3S nanoparticles, while x-ray photoelectron spectroscopy and density functional theory calculations reveal an S-scheme charge transfer pathway driven by the internal electric field. The optimized 6CNMCS photocatalyst achieves a glyceric acid yield of 77.6% and an H₂ evolution rate of 2.89 mmol•g_cat⁻¹•h⁻¹ without sacrificial agents. The enhanced performance is attributed to efficient charge separation and synergistic interfacial interactions that promote xylan adsorption and selective C–H bond activation. Mechanistic studies indicate that carbon-centered radicals and reactive oxygen species cooperatively drive selective C–C bond cleavage toward glyceric acid formation. This work provides a new strategy for integrating biomass valorization with clean hydrogen production.

Pathological cardiac hypertrophy is definitely identified as an adverse deterioration of hemodynamically stressful overload, ultimately heightening risk of sudden death as heart failure (HF) ensues. However, molecular mechanisms underlying cardiac hypertrophy pathogenesis have not been fully described. Herein, we employed targeted genetic approaches and in vivo functional imaging to describe a potent cardiac pro-hypertrophic role of serine arginine protein kinase 3 (SRPK3), one of RNA splicing protein kinases family, which serves as a regulator in pathological hypertrophy and HF. Our study revealed heightened level of SRPK3 in the myocardium of transverse aortic constriction (TAC)-administrated mice and patients who suffer from hypertrophic hearts. Adult mammalian extended expression of Srpk3 in cardiomyocytes (CMs) led to mitochondrial defects and dysfunction, inducing spontaneous concentric hypertrophy and HF, and ultimately premature mortality. Conversely, conditional deletion of Srpk3 in CMs attenuated TAC-induced mitochondrial deficits, consequently ameliorating cardiac hypertrophy and HF. Mechanistically, in canonical splicing regulation, we identified SRPK3- serine/arginine splicing-rich factor 2 (SRSF2)-mediated RNA alternative splicing affecting genes related to mitochondrial function. Also, a noncanonical role of SRPK3 involving binding to RPS3 at Ser¹⁴⁹ to destabilize and degrade PGC1α mRNA was unveiled. Using genetically edited human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we also showed that SRPK3-induced dual pathway coordinately resulted in defective mitochondrial biogenesis and bioenergetics, thus triggering pathological cardiac hypertrophy, as evidenced by the SRPK3-induced rewiring of mitochondrial proteome and impaired heart fueling. In preclinical treatment, intravein injection of adeno-associated virus 9–Srpk3 short hairpin RNA attenuated concentric hypertrophy and HF progression in mice. Together, our findings help to elucidate the mechanism of mitochondrial proteome depletion in triggering hypertrophic hearts, establishing SRPK3 suppression as a long-term and improved strategy for treating pathological cardiac hypertrophy and HF.

The pancreatic adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channel acts as a crucial metabolic sensor, regulating insulin secretion to maintain whole-body energy homeostasis. Gain-of-function mutations in this channel lead to neonatal diabetes mellitus, a rare disorder in which certain mutants exhibit resistance to standard sulfonylurea therapy. Recent studies have identified a centipede toxin, SpTx1, as a potent inhibitor of both human pancreatic K_ATP channels and their gain-of-function mutants. This toxin stimulates insulin secretion, offering a promising therapeutic strategy for neonatal diabetes. However, the molecular mechanism by which SpTx1 inhibits the K_ATP channel has remained unclear. Here, we report the crystal structure of SpTx1 and the cryo-electron microscopy structure of the K_ATP channel in complex with SpTx1. The structure reveals that a single SpTx1 molecule binds to the extracellular surface of the Kir6.2 tetramer. Multiple interactions at the SpTx1–Kir6.2 interface underpin the high affinity and specificity of SpTx1 for human Kir6.2. We demonstrate that SpTx1 inhibits potassium currents by physically blocking the ion conduction pore. Furthermore, a structure-guided search identified another centipede toxin, Sm3a, as a novel K_ATP channel blocker. Together, these findings provide key insights into the inhibitory mechanism of centipede toxins against the human Kir6.2-containing K_ATP channel and establish a foundation for developing these toxins into potential therapeutics for K_ATP channel-related diseases.

Deep learning models are increasingly used to analyze medical images, but their “black box” nature makes it hard to understand the underlying biology and slows down the development of targeted treatments. To tackle this, we built a multi-step approach that combines deep learning analysis of breast magnetic resonance imaging (MRI) with several types of molecular data, including gene activity, protein levels, and genetic information, along with laboratory experiments. Our MRI-based deep learning model accurately predicted whether breast cancer had spread to lymph nodes, and it performed consistently across 3 separate groups of patients. Causal inference using double least absolute shrinkage and selection operator (LASSO) and causal forest double machine learning established a significant effect of NBPF4 expression on the imaging-defined high-risk phenotype, independent of genomic confounders. When we looked at which genes were linked to the imaging-defined high-risk pattern, one gene called NBPF4 stood out because it was supported by all 4 kinds of evidence: imaging features, gene expression, protein data, and genetic association studies. Follow-up experiments in cells and animals showed that boosting NBPF4 activity made tumor cells grow faster, move more, form new lymphatic vessels, and spread to lymph nodes. Mechanistically, NBPF4 worked by activating the mitogen-activated protein kinase (MAPK) signaling pathway and triggering a process known as epithelial mesenchymal transition (EMT). Interestingly, tumors with high NBPF4 were sensitive to drugs that block one part of the MAPK pathway (JNK/p38) but resistant to another part (ERK), suggesting that the pathway had been rewired. Using this insight, computer-based drug screening and further testing identified MK-886 as a promising compound that could suppress NBPF4-promoted MAPK activation and tumor growth. Together, this work traces a complete path from a noninvasive imaging finding to a specific gene (NBPF4) and a potential treatment (MK-886). It establishes the NBPF4–MAPK–EMT axis as a key player in breast cancer metastasis and provides a general framework for turning imaging-based risk predictions into biological understanding and possible therapies.

Red blood cell (RBC) transfusion is a core clinical intervention. However, hypothermic storage induces progressive biochemical, structural, and functional impairments collectively termed the RBC storage lesion (RSL), which compromises post-transfusion efficacy and safety. Conventional RSL detection relies on bulk population-averaged indicators with low physiological relevance and no single-cell resolution, failing to capture cellular heterogeneity and microcirculatory dysfunction. Lab-on-a-chip (LOC) platforms are established with microfluidic technology, and organ-on-a-chip represents a biomimetic and advanced extension of such systems. Together, they enable biomimetic reconstruction of the in vivo microcirculatory microenvironment, high-throughput single-cell analysis, and quantitative assessment of RBC mechanical phenotypes under physiological shear conditions. Distinct from fragmented prior reviews that separate microfluidic engineering from transfusion clinical demands, this work systematically outlines the molecular mechanisms and clinical impacts of RSL alongside unresolved detection bottlenecks, and builds an integrated LOC–endothelium-on-a-chip technical framework covering structural design, biocompatible material screening, and standardized fabrication workflows. It further summarizes microfluidic core applications including single-cell deformability quantification, stiffness evaluation, hemolysis susceptibility testing, microvascular occlusion simulation, and RBC–endothelial interaction analysis. Uniquely, it constructs a tiered translational roadmap integrating microfluidics with multi-omics, artificial intelligence, vascularized multi-organ chips, and function-centered pre-transfusion surveillance, and proposes microfluidic strategies to optimize RBC storage regimens. In summary, microfluidic technology overcomes the limitations of conventional assays for RSL quality control, provides an emerging technical platform for RSL mechanistic research, pretransfusion quality evaluation, and donor-specific precise matching, and promotes the transformation of transfusion medicine from time-based empirical management to function-oriented precision practice.

We investigate thermodynamic crossovers for black holes in the supercritical regime beyond the critical point, where small and large black holes become indistinguishable from the conventional viewpoint. We establish a refined supercritical phase diagram that comprehensively characterizes the phases of small, large, and indistinguishable black holes, delineated by 2 supercritical crossover lines. The universal scaling laws of these crossover lines are fully verified using the thermodynamics of Reissner–Nordström-anti-de Sitter black holes in both the standard framework and the extended thermodynamic phase space, where the cosmological constant is treated as pressure, as well as in 4 other black hole systems. Analogies with supercritical crossovers observed in liquid–gas and liquid–liquid phase transitions are discussed. This work can be extended to more complex black hole backgrounds and offers valuable insights into the fundamental nature of black hole thermodynamics.

Sepsis frequently leaves patients with persistent immune impairment that contributes to late mortality, yet the anatomical routes that transmit this response to the lung remain poorly defined. Here, we identify the spleen as a key extramedullary hub orchestrating pulmonary immune paralysis through a spleen–lung axis. Mechanistically, splenic programmed death-ligand 1 (PD-L1)⁺ polymorphonuclear myeloid-derived suppressor cells undergo TFDP1-driven expansion and migrate to the lungs via CXCL2/CXCR2 signaling, establishing an interorgan immunosuppressive circuit. In the lung, these cells reprogram alveolar macrophages through programmed death-1 (PD-1)-dependent checkpoint signaling, inducing a dysfunctional state characterized by impaired antibacterial responses and enrichment of complement and immune checkpoint pathways. Genetic or pharmacologic disruption of the PD-L1–PD-1 axis restores macrophage function and improves pulmonary host defense in experimental sepsis. Together, these findings define a mechanistic link between splenic myelopoiesis and distal lung immune paralysis.

Hair loss is common and can markedly impair quality of life, yet the contribution of the scalp microbiome to alopecia remains fragmented across disease subtypes and mechanistic levels. This review aims to construct a clinically relevant and mechanistically coherent framework for the scalp microbiome–hair axis. We first summarize the composition and physiological functions of the scalp microbiome, including its roles in barrier integrity, immune regulation, and nutrient metabolism. We then compare dysbiosis patterns across androgenetic alopecia, alopecia areata, seborrheic dermatitis-associated hair loss, and folliculitis/scarring alopecia. This comparison identifies a shared pathogenic layer—barrier disruption, innate immune activation, altered lipid or metabolite processing, and impaired anagen support—together with subtype-selective mechanisms, including immune-privilege collapse in alopecia areata, androgen–lipid–microbiome coupling in androgenetic alopecia, Malassezia-centered inflammatory ecology in seborrheic dermatitis, and infection/biofilm-driven injury with fibrosis in scarring disease. We further organize the available evidence into a 3-tier signaling cascade linking upstream microbial triggers to midstream NF-κB, JAK–STAT, PI3K/AKT, and Wnt/β-catenin integration and downstream outcomes such as stem-cell quiescence, dermal papilla dysfunction, vascular regression, immune-privilege loss, and fibrosis. We also evaluate probiotics, postbiotics, and engineered microbial systems, whose potential benefits may arise from coordinated anti-inflammatory, ecological, regenerative, and pro-angiogenic effects. However, translation is limited by methodological heterogeneity, weak causal evidence, strain stability, targeted delivery, manufacturing quality control, and regulatory uncertainty. Overall, this framework clarifies shared and subtype-specific roles of scalp dysbiosis and defines priorities for precision, microbiome-guided alopecia therapy.

Cancer-induced bone osteolysis is a common complication of multiple malignancies and may actively contribute to bone metastasis. Its core pathology is closely associated with mitochondrial metabolic dysfunction during osteoclast differentiation. In this study, a mitochondrial transplantation strategy based on in situ biomineralization (Mito@ZIF@RGD) was developed to overcome multiple delivery barriers in differentiating osteoclast precursor cells. A zeolitic imidazolate framework-8 (ZIF-8) shell was formed via the in situ self-assembly of Zn²⁺ and 2-methylimidazole on the mitochondrial membrane, thereby enhancing mitochondrial stability. Meanwhile, cyclic RGD (arginine–glycine–aspartic acid) peptides were coordinated with exposed Zn²⁺ sites on the outer shell to promote αvβ3-mediated uptake during osteoclast differentiation. Furthermore, the sustained Zn²⁺ release from the ZIF-8 biomineralization reshaped intracellular ionic homeostasis, thereby improving the durability of therapeutic efficacy following mitochondrial transplantation. In vitro experiments demonstrated that ZIF-8 encapsulation stabilized mitochondria and enabled sustained adenosine triphosphate production for more than 48 h. RGD modification improved cellular uptake efficiency by approximately 55% in differentiating osteoclast precursors, while the mildly acidic microenvironment triggered the coordinated release of mitochondria and Zn²⁺, effectively reducing intracellular reactive oxygen species levels and osteoclast formation. In vivo, Mito@ZIF@RGD treatment promoted the recovery of bone mineral density, suppressed osteoclast surface area formation by approximately 30%, and preserved bone microstructural integrity. Therefore, as a stable, specific, and durable mitochondrial transplantation platform modulating cellular metabolism during osteoclast differentiation, Mito@ZIF@RGD represents a stable and promising platform for the treatment of cancer-induced osteolysis and other metabolic imbalance-associated bone diseases.