Stereotactic body radiation therapy (SBRT) is effective for early-stage non-small cell lung cancer (NSCLC), but the treatment of ultra-central NSCLC (UCNLC) near critical structures remains challenging. This retrospective study analyzed 66 patients with stage I–II unresectable UCNLC who underwent SBRT at Shanghai Pulmonary Hospital (2020–2023). UCNLC was defined by planning target volumes (PTVs) abutting/overlapping vital structures (proximal bronchial tree, esophagus, heart, great vessels, pulmonary vessels) or internal target volumes (ITVs) within 1 cm of these organs. Tailored SBRT plans with non-uniform PTV margins were used in 45.5% of cases, enabling 53.3% of patients to receive a biologically effective dose ≥ 100 Gy. With a median follow-up of 32.2 months, the median progression-free survival (PFS) was 42.9 months; 1- and 3-year PFS rates were 93.9% and 68.8%, respectively. Median local control (LC) and overall survival (OS) were not reached, with 1- and 3-year LC rates of 98.5% and 84.6%, and OS rates of 98.5% and 88.7%, respectively. Toxicities were predominantly grade 1–2, with only one grade 3 pneumonitis. Larger ITV predicted poorer LC and PFS, whereas T stage independently predicted PFS and OS. Therefore, a non-uniform PTV strategy maintained clinical efficacy without compromising safety, supporting its application in UCNLC management.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) was identified by the World Health Organization in 2024 as a key priority bacterium for the development of novel control strategies. While most surveillance studies have focused on clinical isolates, the prevalence and genomic characteristics of CRKP in healthy populations remain poorly understood. Here, we present a nationwide longitudinal descriptive genomic analysis of CRKP isolates from healthy individuals in China in 2016 and from 2019 to 2024. Within this hospital-based health-check cohort, CRKP prevalence was higher in southern regions. Descriptive temporal changes in carbapenemase gene composition were observed, with bla_NDM variants, especially bla_NDM-5, more frequently detected in later years and often associated with IncHI2-IncHI2A plasmids. ST11, primarily represented by capsular types KL47 and KL64, remained the predominant lineage throughout the study period. Gene presence/absence association analysis identified several ST11-enriched loci related to iron acquisition, capsular polysaccharide synthesis, and secretion-associated functions, highlighting candidate lineage-associated features. Comparative genomic analysis with 113 clinical CRKP isolates revealed high genetic similarity (SNP < 100) between some healthy-carrier and clinical strains, suggesting possible clonal relatedness. These findings indicate that healthy individuals in this hospital-based cohort can harbor clinically relevant CRKP, supporting surveillance beyond symptomatic infections while emphasizing the descriptive scope of the present study.

Metastasis remains the leading cause of cancer-related mortality and is increasingly recognized as a consequence of dynamic interactions between tumor cell plasticity and a heterogeneous tumor microenvironment (TME). Rather than being genetically fixed, cancer cells exhibit phenotypic flexibility, enabling reversible transitions among epithelial, mesenchymal, and stem-like states in response to intrinsic programs and extrinsic microenvironmental cues, central to this adaptability. This review synthesizes emerging evidence that tumor progression is governed by reciprocal feedback loops between plastic tumor cells and distinct microenvironmental niches, including hypoxic cores, invasive margins, and perivascular regions. We highlight how stromal components, immune infiltrates, endothelial cells, and extracellular matrix (ECM) remodeling dynamically shape tumor cell states through biochemical and biophysical signals. Advances in single-cell and spatial transcriptomic technologies have revealed the spatial organization and reversibility of these plastic phenotypes, uncovering rare but clinically significant drug-tolerant persister populations. Importantly, we discuss plasticity-mediated therapy resistance as an adaptive, nongenetic process driven by transcriptional and epigenetic reprogramming, metabolic flexibility, ECM stiffening–induced mechanotransduction, and immune-checkpoint plasticity under therapeutic pressure. Together, these findings establish tumor plasticity and microenvironmental heterogeneity as an integrated, evolving system that fuels metastasis and limits durable treatment responses. Targeting this tumor–TME plasticity axis represents a promising strategy to disrupt metastatic progression and overcome therapeutic resistance.

Brain temperature (BT) is a critical physiological indicator closely associated with neurological function and disease progression. However, real-time, noninvasive monitoring of BT remains a challenge due to the limitations of current technologies. Here, we present a novel multimodal framework combining bioheat transfer modeling, deep learning, and computational thermography for accurate BT prediction and imaging. A one-dimensional convolutional neural network was trained on multimodal clinical data, integrating cerebral blood flow, tissue oxygen saturation, and intracranial pressure, achieving a mean absolute error of 0.31°C in BT prediction. The framework incorporates finite element analysis to generate 3D thermographic maps of brain tissue with a spatial resolution of 0.4 mm, validated using MRI-derived data. This approach demonstrated robust performance in predicting localized temperature variations in acute ischemic stroke patients undergoing therapeutic hypothermia, with deviations below 0.45°C. Our findings highlight the potential of this system to enable precise BT monitoring, bridging the gap between computational modeling and clinical neuro-thermometry, and paving the way for advanced diagnostic and therapeutic interventions.

Tethering of lipid droplets (LDs) to mitochondria facilitates fatty acid oxidation and is a key adaptive response that helps cardiomyocytes cope with hypoxia–reoxygenation (HR) stress. However, the molecular mechanisms regulating these interactions during ischemia are not fully understood. We found that HR significantly decreased cardiomyocyte expression and phosphorylation of Rab8a, a small GTPase that interacts with the LD-associated protein perilipin 5 to mediate LD–mitochondria tethering. Using long-chain fatty acid (LCFA) tracking assays we confirmed that loss of Rab8a disrupted physical contact between these organelles to impair the transfer of LCFA from LDs to mitochondria. Furthermore, HR led to the accumulation of intracellular lipids via a combination of both lipolysis and lipophagy, resulting in metabolic stress. To counteract this defect, we evaluated the therapeutic potential of ALY688, a peptide agonist of adiponectin receptors known to stimulate the AMPK–Rab8a signaling axis. Our data indicated that treatment with ALY688 preserved Rab8a expression during HR, thereby maintaining LD–mitochondria interactions and improving metabolic function. These findings uncover a novel Rab8a-dependent mechanism regulating lipid metabolism under ischemic/hypoxic stress and highlight the potential of adiponectin mimetics like ALY688 to mitigate metabolic dysfunction in ischemic heart disease.

Lung adenosquamous carcinoma (ASC) is a rare histological subtype of non-small cell lung cancer (NSCLC), and prospective data regarding the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in this patient population remain scarce. This prospective, multicenter, single-arm phase II trial (NCT04354961) evaluated the safety and efficacy of aumolertinib as first-line treatment for treatment-naïve patients with stage IV EGFR-mutant ASC. Eligible patients received aumolertinib 110 mg orally once daily, with progression-free survival (PFS) as the primary endpoint and objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety as secondary endpoints. The study was terminated early due to slow accrual, with 12 patients enrolled (median age: 66 years; 58.3% male; 58.3% with EGFR exon 19 deletion). After a median follow-up of 29.0 months, the median PFS and OS were 11.1 months (95% CI, 4.27–NA) and 16.7 months (95% CI, 11.3–NA), respectively. Confirmed ORR and DCR were 58.3% and 83.3%. Treatment-related adverse events (TRAEs) occurred in 75% of patients, with 33.3% experiencing grade 3–4 TRAEs; no treatment-related deaths were observed. Aumolertinib exhibits clinical activity with a manageable safety profile in EGFR-mutant ASC patients. However, its reduced efficacy compared with EGFR-mutant adenocarcinoma highlights the need for histology-specific therapeutic strategies.

The incidence of early-onset prostate cancer (EOPC) is rising, and by 2045 a 24.5% increase in cases and a 50% rise in mortality are projected. Accumulating evidence indicates that EOPC represents a distinct disease entity, characterized by unique molecular features, risk factor profiles, and clinical behavior that differ from standard-onset prostate cancer (SOPC). Nevertheless, research in this field remains nascent, and no consensus exists regarding the optimal management of EOPC. We synthesize current evidence on the epidemiology, molecular pathology, clinicopathological characteristics, survival, management, and early detection of EOPC. EOPC exhibits a distinctive molecular landscape, with TMPRSS2–ERG fusions occurring in 63–90% of cases as a hallmark alteration, whereas mutations in PTEN, SPOP, and CHD1 are significantly less frequent. Notably, the prevailing focus on hereditary EOPC has inadvertently led to the neglect of sporadic cases, which dominate clinical practice. Although localized EOPC confers no significant prognostic advantage over SOPC, high-risk or metastatic early-onset disease substantially elevates prostate-cancer-specific mortality. By critically appraising the existing evidence, we identify key knowledge gaps, such as the understudied sporadic EOPC subgroup and the lack of dedicated clinical trials, and propose future research directions to inform early detection and optimize therapeutic strategies for this unique patient population.

Radiotherapy for head and neck cancer commonly induces salivary gland dysfunction, resulting in xerostomia that substantially impairs quality of life after treatment. To identify protective strategies, we established the irradiation-induced submandibular glands (SMG) injury mice model and performed integrated proteomic and metabolomic profiling of gland tissue and saliva. Spermidine levels were significantly altered in irradiated SMG during the postradiotherapy recovery phase. Oral spermidine supplementation restored salivary flow, preserved acinar aquaporin-5 expression, and attenuated vacuolization, apoptosis, and fibrosis in vivo; these effects were validated in SMG organoids. Single-cell RNA transcriptomic analysis further showed that spermidine increased the proportion of acinar cells, enhanced Golgi-mediated secretory gene expression, and suppressed inflammatory cytokine signaling. In the randomized, double-blind, proof-of-concept clinical trial, oral spermidine supplementation during peri-radiotherapy significantly reduced the incidence of xerostomia at 3 months compared with placebo (48.28 vs. 79.31%, p = 0.0391), while increasing salivary output and improving quality of life without serious adverse events. These findings highlight the potential of spermidine as a safe, metabolite-based strategy for preserving salivary gland function and alleviating radiation-induced xerostomia.

Sirtuins (SIRT1–SIRT7) are nicotinamide adenine dinucleotide (NAD⁺) dependent deacylases that serves as metabolic sensors, coupling cellular energy status to chromatin structure, mitochondrial function, and stress responses. Dysregulated SIRT activity has been extensively studied in aging, metabolic syndrome, cardiovascular disease, neurodegeneration, cancer, and immune disorders. However, robust human evidence and SIRT-targeted therapies are lacking. Transgenic mouse models serve as key platforms to study gene function and guide therapeutic development. This review synthesizes evidence from Sirt1–7 transgenic mouse models regarding the core cellular processes governed by SIRTs: metabolism, genome integrity, stress resistance, immunity, and autophagy, and illustrates their operation across different organ systems. By comparing global, tissue-specific, and inducible knockout (KO) and overexpression (OE) models of cardiovascular, respiratory, digestive, nervous, endocrine, urogenital, musculoskeletal, malignant, and immune diseases, we identified central regulatory SIRTs (SIRT1, SIRT3, and SIRT6), context-dependent modifiers (SIRT2, SIRT4, SIRT5, and SIRT7), and their organ- and cell type-specific functions. We also summarize representative small-molecule SIRT activators, inhibitors, and degraders, covering both clinical and preclinical studies, and highlight where contradictions and knowledge gaps remain. Together, these analyses help clarify which aspects of SIRT modulation are most promising and under what isoform, tissue, and disease contexts they should be pursued for the development of SIRT-targeted therapies in human disease.

Metabolic dysregulation is a hallmark of tumorigenesis and profoundly impacts immune surveillance; however, the underlying mechanisms and targeted treatments remain limited in colorectal cancer (CRC). Here, we utilize public databases, mouse models, and multi-omics analyses to identify N-acetyltransferase 1 (NAT1) as a critical prognostic-associated gene that emerges as a significant modulator of tumor immunity in CRC. We demonstrate that NAT1 suppresses glycolysis and lactate production, thereby promoting an immune-activated tumor microenvironment (TME). Mechanistically, NAT1 interacts with enolase 1 (ENO1), a key glycolytic enzyme, acetylating it at lysine 343 (K343) and thereby inhibiting its activity. However, loss of NAT1 in tumor cells leads to enhanced ENO1 activation, which in turn drives glycolysis and lactate production. Lactate then binds to TNF receptor-associated factor 6 (TRAF6), promoting its oligomerization and activation, leading to K63-linked ubiquitination of PD-L1, which enhances PD-L1 stability and facilitates immune evasion. Importantly, low NAT1-expressing tumors from CRC patients show increased sensitivity to anti-PD-1 therapy, and NAT1 deficiency significantly improves the efficacy of anti-PD-L1 antibody treatment in preclinical mouse models. Collectively, our findings highlight the critical role of NAT1 in reshaping the TME and suggest that targeting the NAT1-ENO1-lactate axis represents a promising therapeutic strategy to enhance immunotherapy in CRC.

Macrophages orchestrate immune responses through remarkable phenotypic plasticity, which is intrinsically linked to their ability to reprogram intracellular metabolic pathways in response to microenvironmental cues. While recent advances have highlighted the role of aberrant macrophage metabolism in diverse diseases, a systematic synthesis integrating both intracellular and extracellular metabolic signals remains lacking. This review provides a comprehensive framework for understanding how core metabolic pathways—glycolysis, the TCA cycle, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and amino acid metabolism—are rewired during macrophage polarization under the orchestration of upstream signaling cascades, including NF-κB, PI3K/AKT/mTOR, JAK–STAT, and MAPK. We examine how exogenous metabolites such as succinate, itaconate, lactate, and amino acids reciprocally regulate macrophage function and discuss tissue-specific metabolic signatures of macrophage subsets—including alveolar macrophages (AMs), Kupffer cells (KCs), and tumor-associated macrophages (TAMs)—in the context of obesity, Type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), infections, autoimmune disorders, and cancer. We further evaluate emerging therapeutic strategies targeting macrophage metabolism, summarizing preclinical and clinical advances across signaling pathways, metabolic nodes, cytokines, and cell-based therapies with detailed trial data. By integrating cell-intrinsic metabolic circuitry with extracellular signals, this review establishes a theoretical foundation for metabolism-targeted immunotherapies and identifies key knowledge gaps for future investigation.

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, and the burden is particularly severe in low-income and middle-income countries. Although traditional risk factors such as hypertension, dyslipidemia, diabetes, and smoking have been well established, new research evidence indicates that inflammation, environmental exposure, psychological and social stress, gut microbiota, and genetic susceptibility play a crucial role in shaping the risk profile of CVDs. This review comprehensively summarizes the epidemiology, pathophysiological mechanisms, screening strategies, prevention, and treatment interventions of CVDs throughout the disease development process. Special emphasis is placed on the integration of multiomics methods, artificial intelligence (AI), and digital health technologies (including wearable devices and AI-enhanced electrocardiograms), which are transforming risk prediction and personalized prevention approaches. We also summarize current preclinical and clinical evidence, including ongoing trials, and discuss implementation differences in different socioeconomic environments. Despite significant progress, there are still many challenges in translating new biomarkers and technologies into scalable and equitable clinical applications. This review identifies key knowledge gaps and proposes future directions toward precision cardiovascular medicine, aiming to combine mechanistic insights with practical applications, ultimately reducing the burden of CVDs globally.

Advanced pancreatic ductal adenocarcinoma (PDAC) often progresses rapidly during chemotherapy despite initial assessments of stable disease or partial response by Response Evaluation Criteria in Solid Tumors (RECIST 1.1), underscoring the limitations of the current methods for predicting short-term progressive disease (PD). To address this, the study developed a spatiotemporal deep learning framework that integrates convolutional and long short-term memory (LSTM) neural networks to dynamically predict PD at the next follow-up visit using serial computed tomography (CT) scans and baseline clinical variables. The model was trained on a retrospective cohort of 243 patients (415 predicted events, defined as temporal sequences for the next follow-up PD prediction) and evaluated across internal, external, and prospective cohorts. The model achieved area under the curve (AUC) values of 0.77, 0.76, and 0.74, respectively. Performance remained robust across chemotherapy regimens (AG or Gemcitabine-based, FOLFIRINOX, and SOXIRI; AUC 0.68–0.79), PD subtypes (target lesion growth vs. new metastases; AUC 0.72 vs. 0.77), and baseline disease stages (locally advanced vs. metastatic; AUC 0.85 vs. 0.71). This framework enables the noninvasive, real-time prediction of imminent PD in advanced PDAC, facilitating timely treatment modification. Its validated generalizability and reliance on routine clinical data underscore its potential for seamless integration into chemotherapy management.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, largely due to limitations in early diagnosis and effective treatment. To address these challenges, we developed a multifunctional probiotic nanoplatform, EcNA@Cur-Lip-FA, that integrates real-time diagnosis, targeted therapy, and immune modulation for enhanced CRC treatment. Specifically, this system leverages genetically engineered Escherichia coli Nissle 1917 (EcN) encoding acoustic reporter genes (ARGs) to produce ultrasound (US)-responsive gas vesicles (GVs), enabling real-time, noninvasive tumor imaging. Simultaneously, folic acid (FA)-modified curcumin-loaded liposomes (Cur-Lip-FA) are co-delivered with EcN, enhancing tumor-specific accumulation and therapeutic precision. After being taken up by tumor cells, curcumin is released locally upon exposure to US irradiation, generating reactive oxygen species (ROS), inducing immunogenic cell death (ICD), and activating the cGAS-STING pathway to promote dendritic cells (DCs) maturation and robust CD4⁺/CD8⁺ T-cell responses. Additionally, EcNA@Cur-Lip-FA downregulates angiogenesis-related factors (VEGF, VEGFR1, and ANGPT1), thereby inhibiting tumor neovascularization. In vitro and in vivo studies demonstrated that EcNA@Cur-Lip-FA enables precise tumor localization, dynamic imaging, and effective suppression of both primary CRC and metastatic liver lesions with favorable biocompatibility. This multifunctional platform offers a promising strategy for integrating diagnosis and treatment, paving the way for next-generation CRC theranostics.

Glucose Transporter 1 (GLUT1) is the quintessential facilitator of basal glucose uptake, indispensable for maintaining cellular energy homeostasis, particularly across the blood–brain barrier. Beyond physiological necessity, GLUT1 dysregulation drives a broad pathological spectrum. While genetic haploinsufficiency precipitates severe neurological energy crises like Glut1 deficiency syndrome (Glut1DS), oncogenic networks hyperactivate GLUT1 as the central executor of the Warburg effect to fuel malignant proliferation. Despite its immense therapeutic potential, severe on-target toxicity in normal tissues and adaptive metabolic plasticity remain critical roadblocks to systemic GLUT1 inhibition. This review comprehensively synthesizes GLUT1's multidimensional regulatory networks in health and disease, dissecting how its overexpression fundamentally remodels the tumor microenvironment (TME). We elucidate how GLUT1-driven “metabolic competition” fosters metabolic immune exclusion and drives therapeutic resistance. Furthermore, we map the paradigm shift from traditional systemic blockades to emerging precision interventions. Specifically, we highlight “Trojan horse” glycan-functionalized nanocarriers, targeted protein degradation technologies like PROTACs, and metabolically engineered CAR-T cells. By conceptualizing GLUT1 as the linchpin of the immunosuppressive ecosystem, this work provides a strategic roadmap for precision metabolic immuno-oncology, guiding the development of novel therapies that maximize durable efficacy while minimizing collateral physiological damage.

Coronary microvascular dysfunction (CMD) is a key contributor to myocardial ischemia and cardiovascular diseases. It is characterized by abnormalities of the coronary microvasculature, leading to impaired myocardial perfusion. Although CMD has a high prevalence in patients with nonobstructive coronary artery disease and is associated with adverse cardiovascular events, its pathogenesis has not yet been fully elucidated. Current diagnostic approaches combine noninvasive and invasive methods, but there remains a lack of effective targeted therapies. This review discusses the epidemiology, pathophysiology, diagnostic strategies, and treatment options for CMD, with a particular focus on the protective role of the neuregulin-1 (NRG-1)/v-erb-b2 erythroblastic leukemia viral oncogene homolog B (ErbB) signaling pathway. We initially outline how the NRG-1/ErbB pathway affects endothelial function, ventricular remodeling, oxidative stress, and myocardial angiogenesis, highlighting its potential as a therapeutic target. In addition, we explore emerging evidence that traditional Chinese medicine (TCM) interventions may regulate the NRG-1/ErbB axis to improve microvascular function and cardiac outcomes. Overall, this review deepens our understanding of the mechanisms underlying CMD and provides new avenues for integrated precision therapies, including TCM, with the aim of improving clinical management and prognosis in patients with CMD.

Rheumatoid arthritis (RA) remains a challenging autoimmune disease with variable treatment responses to tumor necrosis factor-α (TNF-α) inhibitors. This study investigates the clinical significance of PD-1^hiCXCR5⁻CD4⁺T peripheral helper (Tph) cells in RA and their potential utility as biomarkers for predicting etanercept (ETN) therapy response. We enrolled 58 RA patients, 12 age- and sex-matched osteoarthritis patients, and 15 healthy controls, with Tph cells quantified by flow cytometry. Among 25 RA patients with inadequate response to conventional synthetic disease-modifying antirheumatic drugs receiving ETN therapy, treatment outcomes were stratified by ACR20 response criteria. Tph cell frequency was significantly elevated in RA patients and correlated positively with multiple disease activity indicators. At baseline, ETN nonresponders exhibited higher Tph proportions than responders (13.23 ± 2.60% vs. 10.82 ± 3.08%, p = 0.0467). Following ETN treatment, responders demonstrated significant Tph reduction (10.82% decreased to 7.97%, p = 0.0105), paralleling serum IL-21 dynamics. In an exploratory analysis, baseline Tph levels showed an association with ETN response. These findings suggest that circulating Tph cells may serve as a candidate biomarker for RA disease activity and therapeutic response monitoring, warranting further validation in larger prospective cohorts.

Obstructive sleep apnea (OSA) is a highly prevalent yet substantially underdiagnosed sleep-related breathing disorder increasingly recognized as a heterogeneous systemic disease rather than a purely mechanical consequence of recurrent upper-airway collapse. This review provides an updated and integrated overview of OSA, spanning epidemiology, multifactorial pathophysiology, heterogeneous clinical presentation, major cardiometabolic and end-organ consequences, diagnostic principles, and evolving personalized management, while also emphasizing the limitations of conventional severity classification, which is predominantly based on the apnea–hypopnea index. We highlight how intermittent hypoxia–reoxygenation, sleep fragmentation, sympathetic activation, intrathoracic pressure stress, endothelial dysfunction, inflammation, oxidative stress, and metabolic dysregulation interact to drive systemic injury, and why physiologically enriched metrics such as hypoxic burden, T90, event duration, sleep-stage dependency, and endotypic heterogeneity may better capture biological risk than event frequency alone. Within this broader framework, fibrosis-linked structural remodeling emerges as an important yet under-supported dimension of OSA pathobiology. Experimental and clinical evidence suggests that OSA may contribute to remodeling of the lungs, liver, kidneys, and heart, although the strength of the evidence and the degree of causal inference vary across organs. By integrating established knowledge with this emerging fibrosis-oriented perspective, this review defines key mechanistic, diagnostic, and translational priorities for future research and phenotype-aware clinical stratification.

Cardiovascular inflammation is increasingly recognized not merely as a secondary response to hemodynamic or metabolic injury, but as a determinant of disease initiation, progression, and remodeling. In the injured heart and vasculature, danger sensing, inflammatory priming, inflammasome activation, nucleic acid recognition, immunometabolic rewiring, immunothrombosis, adaptive immune remodeling, and defective resolution form interdependent circuits rather than isolated pathways. A key challenge is to understand how these circuits shift from adaptive clearance and repair to persistent immune activation, fibrosis, and functional decline. Here, we synthesize evidence on immune landscapes and core inflammatory networks in cardiovascular diseases, focusing on TLR–NF-κB signaling, NLRP3 inflammasomes, cGAS–STING-dependent cytosolic DNA sensing, alternative mitochondrial nucleic acid-sensing platforms, and redox-immunometabolic gating. We highlight mitochondrial quality control and mitochondria-derived DAMPs, including mtDNA, mtROS, ATP, cardiolipin, and oxidized lipids, as an upstream interface linking metabolic stress to sterile immune activation. We further organize disease-specific inflammatory patterns through a stage-cell-threshold perspective across ischemic injury, vascular and metabolic disease, and cardiomyopathic remodeling. Finally, we discuss network-guided therapeutic strategies, translational limitations, biomarkers, endpoints, and safety considerations. This integrated perspective provides a conceptual basis for moving cardiovascular inflammatory therapy from broad suppression toward more precise network regulation.

Retinal neurodegeneration leads to progressive and irreversible vision loss driven by retinal ganglion cell (RGC) death, yet effective neuroprotective therapies remain lacking. Recent studies suggest that small non-coding RNAs play key roles in central nervous system injury, but their relevance to retinal neurodegeneration remains incompletely understood. Here, we identify a significant increase in 5ʹtiRNA-His-GTG, an ANG-generated tRNA-derived fragment, in mouse models of retinal neurodegeneration. Functionally, elevated 5ʹtiRNA-His-GTG promotes reactive gliosis and contributes to RGC degeneration through Müller cell-RGC crosstalk. Conversely, inhibition of 5ʹtiRNA-His-GTG attenuates glial activation, preserves RGC survival, and improves visual function and vision-dependent behaviors. Mechanistically, 5ʹtiRNA-His-GTG induces neurodegenerative changes by suppressing the LPCAT1-mediated phosphatidylcholine (PC) biosynthetic pathway and perturbing glycerophospholipid metabolism. Notably, restoration of LPCAT1 expression or PC levels reverses 5ʹtiRNA-His-GTG-induced neurodegeneration both in vitro and in vivo. These findings uncover a previously unrecognized 5ʹtiRNA-His-GTG-LPCAT1-PC regulatory pathway that contributes to retinal neurodegeneration. Collectively, our study identifies 5ʹtiRNA-His-GTG as a critical mediator of glial-driven neuroinflammation and neuronal loss, and highlights this signaling axis as a potential therapeutic target for retinal neurodegeneration.

The prevailing view of cold tumors as a singular immune-insensitive state is not merely imprecise, which is clinically misleading. Currently, we contend that cold tumors comprise a heterogeneous spectrum of resistance ecosystems by distinct, coexisting, dominant barriers. We argue that a universal “heating” strategy is unlikely to succeed; instead, durable clinical benefit will depend on barrier-directed immune reprogramming. We dissect this heterogeneity by linking a set of core mechanistic drivers to canonical hot, immune-desert, and immune-excluded phenotypes. The drivers include defective antigen processing and presentation, impaired T-cell priming, physical exclusion by aberrant vasculature, stromal components, metabolic exhaustion, and adaptive resistance. Our evaluation of emerging conversion strategies focuses not on their novelty but on capacity to neutralize a specific rate-limiting barrier. We also examine why combination and sequencing are indispensable, highlight translational gaps between preclinical models and human disease and propose a dynamic biomarker framework that extends beyond static PD-L1 assessment to capture real-time shifts in dominant barrier. Our central conclusion is that durable cold-to-hot conversion will require iterative, biomarker-guided and barrier-adaptive interventions that evolve alongside tumor counter-adaptation. The reframing positions immunotherapy resistance not as a terminal obstacle but as a manageable, dynamic challenge, offering a practical strategy for clinical translation.

Macrophages are sentinel innate immune cells that arise from embryonic precursors and bone marrow monocytes, displaying a functional continuum that transcends the classical M1 (pro-inflammatory)/M2 (anti-inflammatory) dichotomy. Under homeostatic conditions, balanced M1/M2 polarization preserves tissue integrity by coordinating immune surveillance, efferocytosis, and tissue repair. When this equilibrium is disrupted, however, M1-skewed responses drive chronic inflammation and autoimmunity, whereas M2-skewed polarization facilitates tumor immune evasion and organ fibrosis. Although diverse therapeutic strategies—including reprogramming, depletion, blockade of monocyte recruitment, CAR-M cells, and nanomedicine—are being explored to restore homeostasis, clinical translation remains constrained by the lack of pathogenic subset-specific markers, insufficient predictive biomarkers for patient stratification, species divergence between mice and humans, and the temporal complexity of context-dependent intervention windows. In this Review, we systematically delineate macrophage plasticity and the molecular mechanisms underlying polarization imbalance, evaluate existing and emerging macrophage-directed interventions, and dissect these translational bottlenecks in depth, highlighting how single-cell multi-omics, humanized models, and dynamic biomarkers can overcome them. By providing a roadmap for precisely calibrating macrophage functional states and restoring M1/M2 balance, this framework will accelerate the development of precision immunotherapies aimed at re-establishing immune homeostasis across a broad spectrum of human pathologies.

Tuberculosis remains one of the leading causes of death from a single infectious pathogen worldwide, despite the availability of antituberculosis chemotherapy and Bacillus Calmette-Guérin vaccination. Tuberculosis pathogenesis is driven by a dynamic and prolonged interplay between host protective immunity and the immune evasion strategies of Mycobacterium tuberculosis (M. tuberculosis). During infection, bidirectional host–M. tuberculosis interactions, together with immunometabolic and epigenetic reprogramming, shape granuloma formation and organization, fibrotic encapsulation, liquefactive necrosis, and ultimately determine disease progression and transmission. However, a systematic framework linking host protective immunity, M. tuberculosis immune evasion, and granuloma evolution across distinct stages of infection remains incomplete. In this review, we summarize the host–M. tuberculosis interactions that shape early innate immune recruitment, adaptive immune activation, granuloma formation and remodeling, persistent infection, granuloma breakdown, and progression to active tuberculosis. We further integrate emerging concepts of metabolic reprogramming, epigenetic reprogramming, trained immunity, tissue-resident immunity, and myeloid-derived immunosuppressive networks. Finally, we discuss how these mechanistic insights may inform the design of next-generation tuberculosis vaccines and adjunctive therapies. This review establishes a comprehensive conceptual framework for understanding tuberculosis immunopathogenesis and provides guidance for the development of antituberculosis vaccines and therapeutic strategies.

Robotic systems are entering clinical care, but full autonomy remains constrained by patient variability, safety requirements, dynamic clinical environments, and the need for professional oversight. Human–robot collaboration (HRC) offers a more realistic path: clinicians retain judgment and responsibility, while robots and AI support sensing, planning, action, and decision-making within defined task boundaries. In this narrative review, we examine recent advances in clinical HRC from a systems perspective, covering system architecture, learning and control, safety mechanisms, autonomy assessment, and real-world deployment. We propose a dual-brain framework, comprising a professional brain for clinical reasoning and decision support, and a physical brain for embodied sensing, planning, and task execution. Using examples from imaging, rehabilitation, surgery, and outpatient care, we argue that clinical autonomy is developing in stages from clinician-supervised imaging and decision support to bounded robotic subtasks and workflow-level coordination, instead of through unsupervised replacement of healthcare professionals. We further discuss how robustness, trust, accountability, and human factors shape safe adoption in practice. By framing autonomy as collaborative rather than substitutive, this review provides a unifying foundation for designing and evaluating the next generation of autonomous clinical systems.

Metabolic reprogramming is a defining feature of cancer and a major contributor to immune escape. Beyond the well-defined glycolysis, dysregulated amino acid and lipid metabolism also regulate tumor growth, stress adaptation, and therapeutic resistance. Amino acids such as glutamine, arginine, tryptophan, methionine, serine, and cysteine shape biosynthesis, redox balance, one-carbon metabolism, epigenetic control, and nutrient competition in the tumor microenvironment. Lipid uptake, de novo lipogenesis, fatty acid oxidation, cholesterol remodeling, COX-PGE2 signaling, sphingolipid metabolism, and ferroptosis further influence antigen presentation, immune cell fitness, and checkpoint regulation. However, most studies still consider these metabolic axes separately, leaving the coordinated amino acid–lipid crosstalk across tumor and immune compartments insufficiently defined. This review synthesizes recent advances in amino acid metabolism, including the glutamine axis, arginine-polyamine biology, the tryptophan–kynurenine–AHR pathway, and methionine-dependent methylation programs. It then discusses lipid metabolic programs that regulate dendritic cell cross-presentation, suppressive myeloid polarization, CD8⁺ T cell exhaustion, PD-L1 palmitoylation, MHC-I stability, and lipid-peroxidation-linked ferroptosis. We further integrate nutrient competition, immunometabolic checkpoints, and dual metabolic targeting strategies with immune checkpoint blockade. This review provides a unified framework for identifying metabolic vulnerabilities, designing rational combination therapies and refining precision cancer immunotherapy.

Alveolar macrophages (AMs) serves as a frontline innate barrier against pulmonary bacterial invasion. The AM pool comprises tissue-resident AMs (TR-AMs) and monocyte-derived AMs (Mo-AMs); yet how vaccination remodels the mixed AM pool for long-term antimicrobial defense against multidrug-resistant bacteria remains poorly understood. In this work, we applied intranasal inactivated whole-cell (IWC) vaccination against Acinetobacter baumannii and systematically dissected AM population dynamics at cellular and molecular levels. Vaccination reshaped the AM pool by recruiting CD11B⁺CD13⁺ Mo-AMs that gradually acquire a TR-AMs-like phenotype and training TR-AMs via sustained transcriptional adaptations. Functionally, the IWC-remodeled AM pool exhibited enhanced antigen presentation, TNF-α secretion, and phagocytosis, accompanied by metabolic rewiring, thereby conferring durable protection against A. baumannii infection. ATAC-seq revealed immune-related chromatin remodeling and enrichment of transcription factors, including ETS, IRF, and bZIP family members. Similar AM pool remodeling was observed following immunization with IWC vaccines against Pseudomonas aeruginosa and Klebsiella pneumoniae, suggesting parallel innate responses across multiple common respiratory bacterial vaccines. Collectively, our study delineates the single-cell transcriptional and epigenetic landscapes of vaccine-remodeled AM subsets, providing mechanistic insights to guide the development of AM-targeted prophylactic vaccines against multidrug-resistant A. baumannii.

EGFR-mutant lung adenocarcinoma (LUAD) is typically associated with an immunosuppressive tumor immune microenvironment (TIME) and poor responses to PD-1 blockade. However, the contribution of drug-tolerant persister cells (DTPs) to immunotherapy resistance remains unclear. We hypothesized that DTPs-derived chemokine (C-C motif) ligand 20 (CCL20) promotes immune evasion and impairs PD-1-based immunotherapy in EGFR-mutant. To test this, humanized NSG mice engrafted with EGFR-mutant H1975 cells and human peripheral blood mononuclear cells (n = 6 per group) were administered with anti-PD-1 (200 µg) and/or anti-CCL20 (20 µg) every other day for a total of four doses. The combination reduced mean tumor volume by 65% compared with control treatment (p < 0.01). Single-cell RNA sequencing showed that cotreatment selectively suppressed CCL20 expression in DTP clusters and activated interferon-α and -γ signaling (ISG15, CMPK2). Multiplex immunofluorescence revealed combination treatment increased infiltration of M1-like macrophages, plasmacytoid dendritic cells, and memory B cells, alongside spatial segregation of CD4⁺ regulatory T cells (p < 0.05). These findings identify DTPs-derived CCL20 as a mediator of immunosuppressive TIME and support combined CCL20/PD-1 blockade as a potential therapeutic strategy for EGFR-mutant lung adenocarcinoma.

Chronic obstructive pulmonary disease (COPD) is characterized by progressive alveolar destruction and defective regeneration, yet the matrix-derived factors contributing to this process remain poorly defined. We investigated the role of elastin-derived peptides (EDPs), bioactive fragments generated during cigarette smoke (CS)-induced elastin degradation, in alveolar epithelial dysfunction. In lung tissues from patients with COPD and in CS-exposed mice, elevated levels of EDPs were associated with elastic fiber disruption and impaired alveolar type 2 (AT2)-to-alveolar type 1 (AT1) differentiation. These observations were supported by histological analyses, single-cell transcriptomic profiling, and organoid-based functional assays. In mouse and human alveolar organoids, CS extract and EDPs each suppressed organoid growth and impaired AT2-to-AT1 differentiation. Mechanistically, EDPs exposure was associated with activation of TLR4/NF-κB signaling, and reduced β-catenin activity, whereas pharmacological inhibition of TLR4 partially restored alveolar epithelial differentiation. Notably, the EDPs-neutralizing agent TB partially rescued AT2-to-AT1 differentiation in organoids and alleviated emphysematous injury in vivo. Together, these findings identify EDPs as an important matrix-derived mediator of alveolar regenerative failure in COPD and support further evaluation of EDP-targeted intervention as a potential strategy for promoting alveolar repair.

Pancreatic ductal adenocarcinoma (PDAC) is refractory to immunotherapy due to its immunologically cold microenvironment and the scarcity of mutation-derived neoantigens. Here, we introduce NeoAPP, a computational tool designed to systematically decode neoantigens arising from tumor-specific transcripts (TSTs) generated by transcriptional dysregulation. By integrating multi-cohort transcriptomic data from 413 PDAC samples, NeoAPP identified a median of 351 neoantigens per sample, originating from 56 neoantigen-encoding TSTs (neoTSTs), exceeding mutation-derived neoantigens in both abundance and patient coverage. Mechanistic analyses show that noncanonical splicing junctions and transposable element activation drive neoantigen generation, while alternative promoter usage regulated by FOXA2 constitutes a potential major source of neoTSTs. In addition, a subset of neoTSTs was detectable in plasma-derived extracellular vesicles and was associated with patient survival, suggesting their potential as minimally invasive biomarkers. Vaccination with neoTSTs induced CD8⁺ T cell responses in HLA-A*02:01 and HLA-A*11:01 transgenic mice and suppressed tumor growth in syngeneic PDAC models. Collectively, this work establishes TST-derived neoantigens as a dominant and therapeutically actionable antigen reservoir in PDAC, advancing a transcriptome-guided framework for neoantigen discovery with potential to overcome immune resistance in low-mutation cancers.

Lymphatic endothelial cells (LECs) line the lymphatic vasculature and support interstitial fluid drainage, lipid transport, and immune-cell trafficking. Beyond these classical functions, recent studies now recognize LECs as heterogeneous, spatially organized endothelial regulators that maintain lymphatic identity while adopting tissue-, segment-, and disease-associated states. Advances in lineage tracing, multiomics, functional imaging, and perturbation studies now link LEC heterogeneity to drainage control, immune surveillance, antigen handling, metabolic homeostasis, and tissue repair. Despite these advances, a unified framework explaining how developmental origin, tissue niche, and context-dependent state transitions collectively shape LEC function across physiology and disease remains lacking. In this review, we summarize the developmental origins, identity-maintenance mechanisms, and anatomical deployment of LEC states across the lymphatic network. We then discuss how specialized LEC states coordinate lymphatic transport, immune surveillance, and peripheral tolerance under homeostasis. We further examine how context-dependent LEC reprogramming contributes to lymphatic disorders, inflammation and autoimmunity, cancer, cardiometabolic disease, and central nervous system dysfunction. Finally, we highlight challenges and opportunities for translational LEC-targeted therapy. Together, this state-centered framework reframes LECs as actionable regulators of tissue homeostasis and disease progression, providing a conceptual foundation for precision lymphatic medicine.

Cancer and cardiovascular diseases, the primary causes of mortality globally, are increasingly understood as biologically interconnected rather than distinct pathologies. Recent evidence indicates that protein homeostasis (proteostasis) functions as a crucial molecular link connecting tumor progression, therapeutic resistance, cardiac remodeling, and treatment-related cardiotoxicity. Proteostasis, which encompasses the cellular processes of protein synthesis, folding, quality control, and degradation, dictates tissue adaptation to chronic stress. Notably, the adaptive mechanisms that allow tumor cells to endure proteotoxic stress and resist therapy are often vital for maintaining cardiac structure and function. Thus, tumor control and cardiovascular injury may be divergent outcomes of a common stress–response framework. In this review, we propose proteostasis as a comprehensive framework for understanding the cancer–cardiovascular interface. We analyze how the ubiquitin–proteasome system, autophagy–lysosome pathway, endoplasmic reticulum stress-induced unfolded protein response signaling, and molecular chaperone networks are differentially reconfigured in cancer and cardiac tissues, influencing tumor survival, therapeutic susceptibility, and cardiovascular dysfunction. Additionally, we explore the translational implications of proteostasis dysregulation, including mechanisms of anticancer therapy-induced cardiotoxicity, emerging biomarkers, cardioprotective strategies, and opportunities for precision cardio-oncology. By conceptualizing efficacy and toxicity as interconnected outcomes of shared proteostasis biology, this review establishes a foundation for developing therapies that optimize cancer control while safeguarding cardiovascular health.

The MYC oncogene family constitutes a master regulatory hub in tumorigenesis, with functional complexity extending far beyond individual gene activities. Recent advances unveil cooperative yet context-dependent antagonism and dynamic interplay among MYC family members, fundamentally reshaping our understanding of lineage specific oncogenic programs. This review synthesizes emerging insights into MYC orchestrated tumor microenvironment remodeling, reciprocal regulation with noncoding RNAs, and the transcriptional and epigenetic governance of metabolic reprogramming. We delineate mechanisms by which MYC drives therapeutic resistance and critically evaluate current strategies targeting MYC or its downstream networks, encompassing direct MYC–MAX disruptors, upstream pathway inhibitors, synthetic lethality, and combinatorial regimens with immune checkpoint blockade or conventional chemotherapy. We further discuss MYC's prognostic significance across diverse cancer types, the critical gap between preclinical efficacy and clinical outcomes, and emerging combination strategies aimed at overcoming acquired drug resistance. By integrating these rapidly evolving biological dimensions, we posit MYC as a highly multidimensional regulatory node whose context-dependent functions present both formidable challenges and promising new opportunities for effective therapeutic intervention.

Type 2 diabetes mellitus (T2D) is a pervasive metabolic disorder driven by insulin resistance and progressive pancreatic β-cell failure, with a rapidly growing global prevalence. Its pathogenesis now extends beyond hyperglycemia to encompass intricate immunometabolic dysregulation, mitochondrial dysfunction, and organelle stress. However, a cohesive synthesis that integrates these disparate molecular mechanisms with contemporary therapeutic advancements remains missing. This review systematically investigates the immunometabolic axis, highlighting macrophage polarization and exosomes, as well as nanotube-mediated crosstalk with β-cells, and describes how mitochondrial dynamics disorder and impaired mitophagy become the core driving factors for β-cell failure. Lipotoxicity mediated by ceramides, diacylglycerols, and cholesterol imbalance is critically analyzed alongside proteotoxicity from islet amyloid polypeptide aggregation. We then chart the therapeutic evolution from glucocentric strategies to modern complication-centric paradigms, emphasizing SGLT2 inhibitors and GLP-1 receptor agonists that confer proven cardio-renal protection. Personalized treatment, multiomics integration, next-generation precision therapies, and holistic art-based interventions that promote sustainable lifestyle changes are further discussed. By connecting molecular insights to clinical application, this review provides a comprehensive resource for researchers and clinicians, aiming to advance T2D management and improve global patient outcomes.

Antibody–drug conjugates (ADCs) and peptide–drug conjugates (PDCs) are modular targeted therapeutics in which molecular recognition is coupled with controlled payload delivery. Owing to their high specificity and precision, they have been regarded as a transformative paradigm for cancer therapy. In this review, current understandings and future perspectives of ADCs and PDCs are synthesized across rational design principles, historical evolution, clinical translation, and emerging formats, aiming to improve practical comprehension and application in oncology. Key determinants of performance: target selection, antibody or peptide carrier attributes, linker stability and cleavage mechanisms, payload classes, and conjugation strategies, are additionally discussed. Milestone advances achieved spanning hematologic malignancies and solid tumors are emphatically summarized to provide a framework by which future conjugate development may be contextualized. In parallel, the expansion of PDCs as complementary platforms is outlined, and advantages are highlighted, while limitations are also considered. ADCs and PDCs still face challenges such as toxicity, resistance, and poor stability. However, through breakthroughs including linker optimization, novel payloads, bispecific designs, and AI-driven approaches, future conjugated drugs will continue to evolve toward personalization, combination therapies, and broader indications. This article provides a systematic synthesis of extant research, thereby facilitating the future advancement of targeted conjugate drugs toward greater precision and individualization. It holds significant academic value as a reference resource and offers practical guidance for the development of novel antineoplastic therapeutics.

We explored the epigenomic effects of vegan diet (VD) versus meat-rich diet (MR) and identified mechanisms that help to explain how VD affects epigenetic gene regulation. Genome-wide DNA methylation profiles in 48 healthy individuals were investigated after a 1-month randomized isocaloric dietary intervention comparing effects of a VD versus a MR. Genome-wide DNA methylation analysis revealed changes in differentially methylated positions following dietary intervention, with the VD group showing a higher degree of gene-promoter silencing in cancer-related pathways and cell growth-associated pathways (mTOR and Hippo). Cell type deconvolution indicated an anti-inflammatory shift in the VD group, characterized by decreased neutrophils and increased CD4⁺ T-cell proportions, aligning with whole blood count data. Pathway analysis reflected changes in gene promoter methylation consistent with macronutrient changes according to the diets, in that VD silenced lipid metabolism and increased insulin pathway genes. Interestingly, the health-outcome-trained epigenetic clocks PhenoAge and GrimAge indicated a deceleration of biological aging in the VD group, while the chronologically optimized Blood&Skin clock showed an opposing acceleration. Convergent evidence from pathway analysis and health-outcome epigenetic clocks thus suggests that a 1-month VD drives epigenomic changes associated with reduced cancer risk and decelerated biological aging.

Resmetirom is a liver-directed, thyroid hormone receptor β (THRβ)-selective agonist approved for treating metabolic-associated steatohepatitis (MASH). While Resmetirom hepatocyte-specific effects are well-established, its impact on other hepatic cells, particularly hepatic stellate cells (HSCs), the main fibrogenic cells, remains unknown.

Using animal models, immortalized cell lines, and primary murine and human HSCs, we combined pharmacological treatments with genetic manipulation of THRα and fatty acid amide hydrolase (FAAH) to examine the effects of Resmetirom. Resmetirom ameliorates MASH through actions in both hepatocytes and HSCs. The overexpression of solute carrier organic anion transporter family member 1B1(SLCO1β1) in both cell types increases the efficiency of Resmetirom. THRα expression is higher in HSCs than in hepatocytes in both human and murine cells. Resmetirom attenuates TGF-β1-induced HSC activation via THRα and increased FAAH expression and activity, while their inhibition prevents Resmetirom from reducing fibrotic marker expression and the elevated glycolytic activity typical of activated HSCs.

These results uncover an unrecognized mechanism of action for Resmetirom, demonstrating that its antifibrotic efficacy extends beyond hepatocytes to include direct effects on HSCs via THRα and FAAH. These results may support the development of future therapeutic strategies aimed at THRα in HSC, in combination with existing approaches targeting hepatocyte THRβ.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with chemotherapy response evaluation currently relying on the Response Evaluation Criteria in Solid Tumors (RECIST). However, RECIST inadequately captures the unique biology of PDAC, particularly stromal fibrosis–induced radiographic pseudoprogression. We developed and externally validated a multivariable prognostic prediction model, the chemotherapy Progression Decision (cPD) score, integrating biological markers and imaging metrics to guide therapeutic decision-making after the first RECIST assessment. This multicenter retrospective study enrolled 616 PDAC patients across three cohorts: the Training Cohort (n = 155), Validation Cohort 1 (n = 263), and Validation Cohort 2 (n = 198). Multivariable Cox regression identified four independent prognostic predictors: neutrophil-to-lymphocyte ratio, baseline carbohydrate antigen 19-9, tumor maximum cross-sectional rate change ratio, and emergence of new lesions. These were integrated into an integer-based score (8–13 points) stratifying patients into good prognosis (GP), poor prognosis (PP), and critical prognosis (CP) groups. The cPD model demonstrated robust discrimination and calibration, with significant survival differences across groups in all cohorts. Notably, the cPD score identified a subset of patients (GP and PP groups) for whom continuing the original chemotherapy yielded significantly better survival than switching regimens, even when RECIST classified the disease as progressive.

The SARS-CoV-2 Omicron variant is more contagious than the original Alpha variant and can still cause neurological symptoms, including cognitive impairment. To gain a deeper understanding of the molecular mechanisms underlying these neurological effects, this study was conducted. Proteomic and phosphoproteomic analyses were carried out utilizing LC-MS/MS. Samples included brainstem, cerebellum, frontal lobe, occipital lobe, parietal lobe, and temporal lobe from SARS-CoV-2 Omicron-infected and noninfected control rhesus macaques. Infection with Omicron resulted in inflammatory responses across all six brain regions, and significant regional-specific molecular alterations were observed. Proteomic and phosphoproteomic analyses revealed extensive abnormalities in immune activation, synaptic function, DNA repair, and signaling pathways across different brain regions. We further predicted key kinases and identified candidate proteins with significantly altered expression. This study reveals region-specific inflammatory and signaling signatures in the brain following Omicron infection. The recognized kinases and proteins with abnormal regulation serve as potential candidates for drug discovery. This can aid in formulating new therapeutic approaches for neurological issues related to COVID-19.

Acute severe lower respiratory tract infections (asLRTIs) pose a significant clinical challenge, especially in critically ill patients, but the role of the lower respiratory tract microbiome (LRTM) remains unclear. This study aimed to characterize LRTM composition and host immune factors to identify prognostic features of clinical outcomes. The study included 53 asLRTI patients and 35 controls. Metagenomics, metabolomics, proteomics, and RNA sequencing were conducted, while analysis of similarities (ANOSIM) and Cox regression were performed for statistics. Clinical data, including pneumonia severity scores, were collected on BALF sampling, with a 100-day follow-up. LRTM samples were grouped into five clusters (C1–C5). Cluster C5 resembled controls, while others showed significantly lower diversity. LRTM composition correlated with prognosis, with higher pathogenic bacteria abundance linked to poorer outcomes. Cluster C3 was associated with poor prognosis and reduced survival. Metabolite analysis revealed elevated α-ketoisocaproic acid in asLRTIs and higher 10-nitrolinoleate in poor-prognosis patients. Immune responses varied across clusters, with distinct gene and cytokine expression patterns. Cluster C1, associated with Acinetobacter baumannii, exhibited heightened IL17 pathway activation. LRTM composition in asLRTIs is linked to clinical outcomes, with no single gradient of difference but distinct community states characterized by varying pathogens, metabolites, and immune responses.

While it has been reported that antioxidant selenoproteins are crucial for anti-ferroptosis in tumors, it remains unclear whether and how biosynthetic dysregulation of selenoproteins promotes resistance to ferroptosis. By bioinformatics analysis and in vitro confirmatory assays, we screened and identified selenophosphate synthetase 2 (SEPHS2), a key enzyme in a selenoprotein synthesis cascade, as a potential candidate for promoting anti-ferroptosis in tumors. We found that the expression of SEPHS2 was upregulated upon treatment with ferroptosis inducers. Knockdown of SEPHS2 inhibited tumor proliferation, migration and invasion, as well as attenuated selenoprotein biosynthesis to sensitize tumor cells to ferroptosis. Furthermore, our results demonstrated that activating transcription factor 4 (ATF4), a ferroptosis-related transcription factor, might work as a direct upstream regulator to activate SEPHS2 transcription. Downregulation of ATF4 enhanced sensitivity to ferroptosis, whereas restoration of SEPHS2 expression rescued this effect, suggesting that ferroptosis resistance might be regulated by the ATF4/SEPHS2 axis. Notably, for the in vivo assay, knockdown of either SEPHS2 or ATF4 exhibited the optimal repression of tumor growth when combined with ferroptosis inducers. Thus, our findings highlight that inhibition of ATF4/SEPHS2 signaling might contribute as a novel adjuvant therapeutic strategy to improve the efficacy of ferroptosis-based treatment in tumors.

Time-restricted feeding (TRF) is a promising dietary strategy for delaying metabolic aging, yet its efficacy in cardioprotection across metabolic stages remains poorly understood. This study demonstrates that a 10-h TRF window significantly mitigates cardiac aging phenotypes including fibrosis, mitochondrial dysfunction, and senescence-associated secretory phenotype in prediabetic mice, whereas these protective effects are largely blunted at the diabetic stage, despite improving systemic metabolism in both prediabetic and diabetic models. Mechanistically, TRF acts as a chronotherapeutic cue that restores the diurnal oscillations of short-chain fatty acid (SCFA)-producing gut microbiota. These rhythmic SCFAs serve as peripheral “metabolic zeitgebers” that resynchronize cardiac diurnal rhythms autophagy. In vitro, SCFAs enhance autophagic flux and preserve mitochondrial integrity in senescent cardiomyocytes. Crucially, the cardioprotective benefits of TRF are largely abolished in p62-deficient mice, identifying p62-dependent autophagy and mitochondrial homeostasis as a key molecular mechanism underlying TRF efficacy. In overt diabetes, the loss of TRF-mediated protection is attributed to a profound “metabolic rigidity” that prevents restoration of autophagic rhythmicity. Overall, our findings reveal that TRF prevents cardiac aging by entraining the gut microbiota–SCFA–cardiac p62 axis during the prediabetic stage, highlighting a critical metabolic window for dietary intervention.

Reactive cutaneous capillary endothelial proliferation (RCCEP) is the most common immune-related adverse event associated with camrelizumab and has been linked to favorable outcomes. We conducted a pooled analysis of two phase III randomized trials, ESCORT (NCT03099382) and ESCORT-1st (NCT03691090), to evaluate the clinical characteristics and prognostic relevance of RCCEP in patients with advanced esophageal squamous cell carcinoma (ESCC) receiving camrelizumab-based therapy. A total of 526 patients treated with camrelizumab, either alone or in combination with chemotherapy, were included. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to RCCEP status. Inverse probability of treatment weighting (IPTW) was applied to adjust for baseline imbalances, and a 2-month landmark analysis was performed to reduce lead-time bias. Overall, 420 patients (79.8%) developed RCCEP, mostly grade 1–2 (99.0%), with no RCCEP-related treatment discontinuations. The median onset was 1.18 months, and the duration was 3.12 months. RCCEP-positive patients showed a higher ORR (52.4% vs. 26.4%), longer PFS (5.55 vs. 1.94 months; HR = 0.45), and OS (13.40 vs. 6.11 months; HR = 0.47), consistent after landmark analysis. These findings suggested that RCCEP was frequent yet manageable and may serve as a potential on-treatment biomarker of camrelizumab benefit in ESCC.