Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with high rates of post-resection recurrence posing significant clinical challenges. Early recurrence is largely driven by aggressive tumor biology, while late recurrence reflects de novo carcinogenesis in a cirrhotic liver. Traditional clinical and pathological predictors are insufficient for accurately identifying high-risk patients. Emerging translational advances including genomic, transcriptomic, proteomic, and metabolomic biomarkers; liquid biopsy techniques; artificial intelligence (AI)-driven histological and radiomic analyses offer new avenues to refine recurrence risk stratification and guide perioperative therapy. Simultaneously, the shifting etiological landscape from viral hepatitis to metabolic dysfunction-associated steatohepatitis (MASH) and alcohol-related liver disease underscores the need for tailored surveillance and preventive strategies. Advanced technologies such as single-cell and spatial transcriptomics provide unprecedented insights into fibrosis progression and tumor evolution. Integrating these approaches may enable personalized surveillance protocols and therapeutic interventions, optimizing outcomes for HCC patients and reducing unnecessary resource utilization.

Background: Gastrointestinal tract cancer (GIC), including oesophageal cancer (EC), gastric cancer (GC) and colorectal cancer (CRC), is characterised with high global incidence and mortality rates, with similar tumourigenic processes. However, the common and heterogeneous molecular features among GIC at single-cell level remain poorly characterised.

Methods: Single-cell RNA-seq data of more than one million high-quality annotated cells from 577 specimens, including 121 ECs, 182 GCs and 254 CRCs, were integrated to systematically decipher the heterogeneous characteristics of GIC. Non-negative matrix factorisation (NMF) was employed to identify epithelial cell meta-programs (MPs), and cell–cell communication analysis was conducted to investigate regulatory interactions between the tumour microenvironment (TME) and these MPs. Additionally, cell lineage inference analysis was performed to identify metaplastic signatures in EC and GC.

Results: We identified 24 consensus MPs from epithelial cells and 42 distinct subtypes from non-epithelial cells thus offering a comprehensive overview of heterogeneous characteristic in GIC. Notably, we observed that EC exhibited unique features, including heightened activity in stress-related programs and a more exhausted TME, enriched with CD4+ Tregs and CD8+ exhausted T cells. In contrast, epithelial cells in GC displayed increased expression of epithelial–mesenchymal transition (EMT)-related signatures and an activated immune phenotype, marked by enrichment of NK cells and CD8+ effector T cells. Moreover, samples with metaplastic signatures in GC and EC showed similarities to CRC, including elevated expression of metabolism-associated signatures and an abundance of CD4+ helper-like T cells. Finally, we identified the potential regulatory roles of the TME in shaping epithelial cell behaviour.

Conclusions: Our findings provide insights into the common and specific cellular and molecular patterns associated with GIC tumourigenesis and TME remodelling. We also elucidate the similarity between GC/EC with metaplastic signature and CRC, which advancing our understanding of these malignancies.

Nonsmall cell lung cancer (NSCLC) is a lethal cancer and lacks robust biomarkers for noninvasive clinical diagnosis. Detecting NSCLC at the early stage can decrease the mortality rate and minimise harm caused by various treatments. We curated 2050 samples from public tissue and plasma datasets including both invasive and noninvasive types, then supplemented with in-house pooled plasma and exosome samples. Eleven independent transcriptome datasets were utilised to develop a new machine learning model by integrating PIWI-interacting RNA (piRNA) to predict NSCLC. Five piRNA signatures derived from ribosomal subunits identified to be tumour-specific exhibited robust diagnostic ability and were combined into a piRNA-Based Tumour Probability Index (pi-TPI) risk evaluation model. pi-TPI effectively distinguished NSCLC patients from healthy individuals and showed efficacy in identifying early-stage cancers with Area under the ROC Curve (AUC) values over .80. Plasma cohorts exhibited the diagnosis efficacy of pi-TPI with an AUC value of .85. Experimental exosomal data enhances the accuracy of diagnosing noncancerous, benign, and cancer cases. The pi-TPI marker in the noncancer/cancer subgroup exhibited superior predictive performance with an AUC value of .96. These findings underscore the significant clinical potential of the five piRNA signatures as a powerful diagnostic tool for NSCLC, particularly of noninvasive cancer diagnostics.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with few well-established risk factors. Emerging epidemiological evidence suggests a link between hepatitis B virus (HBV) infection and PDAC. However, the underlying mechanisms remain unclear.

Methods: High-throughput sequencing-based approach was employed to identify HBV integrations in tumour and para-tumour tissues of PDAC. The biological functions of KMT2B were evaluated in PDAC cell lines as well as in subcutaneous and orthotopic mouse models of PDAC. Chromatin immunoprecipitation sequencing and RNA sequencing were used to identify the pathway involved in PDAC development.

Results: HBV integration was detected in approximately one-third of HBV DNA-positive PDAC and adjacent para-tumour tissues. A total of 425 viral‒host junctions were identified, with the majority located in intergenic regions (51.29%), followed by introns (43.29%) and exons (2.35%) of the human genome. Lysine methyltransferase 2B (KMT2B, also known as MLL4), a gene frequently targeted by HBV integration in hepatocellular carcinoma, was also found to be interrupted by HBV in PDAC. KMT2B was significantly upregulated in PDAC and promoted malignant behaviours both in vitro and in vivo. Mechanistically, KMT2B exerts its oncogenic effects by regulating the downstream target gene FYN through histone H3K4 trimethylation, leading to the activation of the PI3K/Akt signalling pathway.

Conclusion: HBV integration is a common event in HBV-related PDAC and KMT2B has been identified as a novel PDAC-related gene.

Background: Colorectal cancer (CRC) ranks among the most prevalent malignant tumours of the digestive system globally and is associated with unfavourable survival outcomes. The exhaustion of CD8⁺ T cells serves a crucial role in facilitating tumour immune escape. Yet, the dynamic evolution of CD8⁺ T cell exhaustion and its impact on clinical prognosis across TNM (tumour-node-metastasis) stages in CRC remains incompletely characterized.

Methods: Tumour and adjacent tissues (20 samples total) from 6 CRC patients spanning diverse TNM stages were analyzed using integrated single-cell transcriptomic profiling (scRNA-seq), single-cell T cell receptor/B cell receptor sequencing (scVDJ-seq), and spatial transcriptomics. T cell exhaustion markers, immune clonality, gene expression profiles, and the spatial distribution of both tumour cells and immune cells were systematically profiled. Functional enrichment and intercellular communication analyses were conducted. Key findings were validated using immunofluorescence and public datasets.

Results: Our results illustrate how advancing TNM stages in CRC shape CD8⁺ T cell exhaustion through divergent TNFRSF18/CXCL13 dynamics and ribosomal stemness. TNFRSF18 expression was notably higher in T cells infiltrating tumour tissues relative to their counterparts in adjacent non-tumorous areas, with high-expressing CD8⁺ T cells exhibiting marked exhaustion features. During CRC progression, TNM-stage-driven remodelling of the tumour microenvironment (TME) induced progressive CD8⁺ T cell exhaustion marked by declining TNFRSF18 and rising CXCL13 expression in tumour-infiltrating T cells elevation of both markers in the tumour compared with adjacent tissues. Moreover, we show that tumour cells displayed elevated expression of stemness-associated ribosomal genes (RPS7, RPL8, RPL30), peaking at stage T4, which correlated with poor prognosis and immune escape.

Conclusions: This integrative multi-omics study uncovers CD8⁺ T cell exhaustion dynamics and ribosomal stemness-mediated immune evasion across CRC progression. CXCL13, TNFRSF18, and ribosomal proteins (RPS7/RPL8/RPL30) are identified as novel biomarkers with direct prognostic value and therapeutic relevance, providing therapeutic targets for precision immunotherapy in CRC.

Lung cancer remains the leading cause of cancer-related death in both women and men in the United States and globally. Even among early-stage patients who undergo surgical resection, a significant portion of patients develop metastases. Notably, approximately 30% of patients with stage I lung cancer experience relapse. For decades, protein-coding genes dominated cancer research, driven by the belief that these genes were the primary contributors to tumorigenesis. Despite advances in treatment our understanding of fundamental mechanismsdriving lung cancer progression remains limited. The overall 5-year survival rate for all stages of lung cancer combined is approximately 20%. Surgical resection remains the best option for early-stage diseases, whereas chemotherapy, immunotherapy or combination therapies are primarily employed in advanced stages. Frequent treatment failure due to therapy resistance, highlight the urgent need to identify novel biomarkers for early diagnosis, prognosis, and the development of more effective therapies. This underscores the necessity and urgency of researching lncRNAs. The advent of next-generation sequencing and other high-throughput technologies guided the discovery of a new class of molecules, non-coding RNAs (ncRNAs) that play a role in many aspects of cellular physiology. Among the various types of ncRNAs, long non-coding RNAs (lncRNAs)—which have transcripts longer than 200 nucleotides—have emerged as key regulatory molecules in a myriad of cell functions by interacting with DNA, with other RNAs, including mRNA, miRNA and with proteins. Importantly, lncRNAs play crucial roles in cancer progression, including metastasis by activating oncogenic pathways, promoting epithelial-mesenchymal transition, remodelling the extracellular matrix, and inducing angiogenesis. Notably, they can function as both oncogenes and tumour suppressors. MALAT1 is one of the lncRNAs that contribute to metastasis and resistance to tyrosine kinase inhibitors in lung cancer. This review summarizes the role of lncRNAs in cancer, with a specific emphasis on their contributions to lung cancer metastasis.

Background: Naïve T cells are maintained in a quiescent state prior to activation. As inappropriate T-cell activation can lead to impaired immune tolerance and autoimmune diseases, the transition from quiescence to activation must be under strict regulation. Despite its importance, the mechanisms underlying the maintenance of the quiescent state remain incompletely understood.

Methods and Results: Through multi-omics integration analysis, we reveal that INPP4B, a phosphatase of the phosphoinositide 3-kinase pathway, is highly expressed specifically in T cells and is involved in suppressing T-cell activation and maintaining quiescence. Our findings uncover that INPP4B forms a T-cell-specific chromatin interaction domain and exhibits high expression levels in quiescent T cells. Upon T-cell activation, both the chromatin interaction and expression levels of INPP4B decrease. Functional studies further confirm that INPP4B suppresses T-cell activation and effector functions. Additionally, we observe increased expression level of INPP4B in exhausted T cells within the tumour microenvironment.

Conclusion: These results highlight the importance of maintaining optimal levels of INPP4B for T-cell function. Our findings suggest that INPP4B could be a potential target for enhancing the efficacy of T-cell-mediated immune responses against tumours.

Background: One in five adults aged 40 will develop heart failure (HF) during their lifetime. Risk factors (e.g., hypertension, diabetes mellitus, coronary artery disease, etc.) lead to structural and functional changes in cardiomyocytes, resulting in HF. At the cellular level, these changes consist of mis/over-expression of genes that regulate cardiac identity (e.g., CamK2δ, PKC, Stat3, etc.). The current paradigm for treating HF is pharmacological or device-based intervention; however, with few exceptions, the condition worsens with time. We are proposing to implement a change in HF treatment, shifting from a drug-centric system to a cardiac target-specific molecular approach that would reverse hypertrophy and adverse remodelling of affected cardiomyocytes.

Methods: A cardiomyocyte targeting peptide (CTP) was reversibly linked to miRNA106a for delivery to a mouse model of HF. Reversal of morphological, signalling, and physiological HF parameters was measured. Additionally, CTP-miRNA106a was introduced into a human cardiomyocyte cell line to identify mechanism(s) at play for reversing HF characteristics (e.g., hypertrophy).

Results: Bio-distribution studies showed that intravenously injected CTP-miRNA106 delivered its cargo specifically to the heart within 30 min, followed by clearance of CTP from the heart to the kidneys, and to a lesser extent, the liver by 35 h with persistence of miRNA106a in cardiomyocytes until day 7 (the latest tested time-point). CTP-miRNA106a reversed angiotensin2/isoproterenol-induced hypertrophy in 90% of the treated mice. We also identified two potential HF intracellular signalling pathways/mechanisms (PLCβ1/PKC/IP3 and NF-κB) targeted by CTP-miRNA106a that could benefit many pathophysiologies underlying HF, including inflammation.

Conclusions: CTP-miRNA106a, a first-of-a-kind cardiac-specific drug, downregulates genes involved in cardiac hypertrophy and inflammation through the PLCβ1 and CamKIIδ kinase pathways. CTP delivery of miRNA106a cargo is specific to cardiomyocytes both in vitro and in vivo, and once delivered, many HF parameters, including hypertrophy, are reversed.

Background: Myasthenia gravis (MG) is an autoimmune disease predominantly driven by autoantibodies targeting acetylcholine receptor (AChR), resulting in muscle weakness. Efgartigimod, a neonatal Fc receptor (FcRn) blocker, reduces pathogenic immunoglobulin G in anti-AChR antibody-positive generalised MG (gMG). This study aimed to identify immune mechanisms underlying MG pathology and response to efgartigimod.

Methods: We constructed a single-cell atlas of peripheral immune cells from treatment-naïve and efgartigimod-treated patients with gMG. Comprehensive immunophenotyping was performed to compare the clonal diversity of B- and T-cell populations, alongside experimental validation to assess the activation of Th17-related pathways before and after FcRn blockade.

Results: B cells in patients with gMG exhibit heightened activation and differentiation, while T cells display distinct pro-inflammatory phenotypes. Enhanced intercellular signalling contributed to the pathogenicity associated with gMG. Efgartigimod mitigated upregulated antigen processing and presentation pathways in MG. Additionally, B-cell clonal diversity and IGHG1-bearing B-cell receptors increased. Transcriptional factor alterations were noted in suboptimal responders. Regulation of T-cell activity, particularly within Th17-related pathways, was associated with remission rates.

Conclusions: These findings underscore immune heterogeneity and dynamics during efgartigimod treatment, providing mechanistic insights into therapeutic response in gMG.

Background: The progression and prognosis of early-stage lung adenocarcinoma are closely associated with histologic subtypes, yet the presence of mixed histologic patterns often complicates prognostic assessment. Currently, the correlation between molecular and histologic features remains poorly understood.

Methods: Formalin-fixed paraffin-embedded (FFPE) samples were collected from patients with primary early-stage lung adenocarcinoma, encompassing three histologic subtypes: well-differentiated, moderately differentiated, and poorly differentiated. The GeoMx Digital Spatial Profiler platform was utilized to obtain spatial transcriptomic profiling. Regions of interest were carefully selected and further subdivided into three categories of areas of interest, specifically epithelial cell-enriched regions, macrophage-enriched regions, and other regions. Multiplex immunofluorescence (mIF) assays were employed to validate the obtained results.

Results: Distinct molecular characteristics were identified in tumor epithelial- and macrophage-enriched compartments spanning well-differentiated to poorly differentiated tumors. In poorly differentiated tumors, we observed enrichment of pathways related to humoral immune response, complement activation regulation, and extracellular matrix receptor interaction pathways, all of which are significantly associated with poorer prognosis. We integrated these pathways to develop a composite molecular signature that strongly correlate with adverse prognosis.

Conclusions: Our results provide new insights into the link between molecular and histologic subtypes in mixed-type lung adenocarcinomas. Specifically, the identified molecular signatures offer potential biomarkers for predicting disease progression and prognosis, thus facilitating more precise and personalized therapeutic approaches.

Chromatin relaxation is a permissiven progress for DNA repair through enabling repair factors to access the damaged DNA. Linker histone H1 is important in maintaining chromatin compaction under physiological state. The recent evidence highlights the importance of H1 modifications in response to cellular stress. Following DNA double-strand breaks, the metabolic enzyme phosphorylated CTP synthase 1 (CTPS1) functions as a deamidase, catalyzing the rapid conversion of H1 residues Asn76 and Asn77 into aspartate. This modification enables subsequent acetylation at Lys75 by the histone acetyltransferase p300, thereby reducing H1-DNA affinity and promoting chromatin decompaction. This sequential modification-H1 deamidation followed by acetylation-facilitates the recruitment of repair factors involving both homologous recombination and non-homologous end joining repair pathways, and consequently promoting DNA repair. Importantly, high expression of CTPS1 is associated with resistance to radiotherapy in mouse models and clinical cancer patients, suggesting that the CTPS1 may serve as a potential therapeutic target. While targeting CTPS1 may offer opportunities to enhance radiosensitivity of cancer patients, challenges related to specificity and off-target effects require further studies. This article highlights an emerging role of H1 modification in the DNA damage repair and discusses the therapeutic potential of manipulating H1 deamidation in cancer treatment.

CD31 (PECAM-1) plays a critical role in T cell migration, whilst its immunoreceptor tyrosine inhibitory motifs (ITIMs), Y663 and Y686, are recognised for their roles in endothelial function, the precise mechanism in regulating immune cell remains elusive. Here, we demonstrate that CD31 is essential for Treg migration. Upon ITIM engagement, CD31 activates and interacts with the protein tyrosine phosphatase SHP2. In vivo, CD31 Y663F gene transfer recapitulates the wild-type migration phenotype, driven by a metabolic switch to fructose utilisation under the regulation of the PFKFB3 gene. Conversely, the Y686F mutation impairs Tregs migration by disrupting both glycolysis and the switch to fructose metabolism, thus promoting the mitochondrial function via activation of the RNF111/OGT pathway. Our findings reveal a novel role for CD31 ITIMs in orchestrating a metabolic that is switch crucial for Treg migration. This understanding of CD31 polymorphisms and their impact on Treg migration offers potential therapeutic avenues for autoimmune diseases, particularly rheumatoid arthritis (RA).

Background and Aims: The pancreatic tumour microenvironment (TME) is a complex ecosystem where tumour cells, cancer-associated fibroblasts and immune cells interact, often in ways that contribute to tumour growth. The role of interleukin (IL17)A in pancreatic cancer progression is now more defined, and it is known to sustain a pro-tumoural microenvironment and inhibit the immune response. Here, we explore the effect of combining IL17A depletion with a cancer vaccine to enhance anti-tumour immunity.

Methods: We used genetically engineered mice proficient or deficient in IL17A, and orthotopically injected mice with pancreatic tumour cells depleted or not in IL17A, to examine the vaccine effects on tumour growth and immune responses. Both humoral and cellular immune responses were analysed following vaccination in IL17A-deficient and control mice.

Results: Mice lacking IL17A—either genetically or through pharmacological depletion—exhibited prolonged survival and smaller tumours, compared to vaccinated controls. Vaccination in IL17A-deficient mice significantly increased the influx of immune cells, including Natural Killer (NK) and effector/memory CD8 T cells, which displayed higher cytotoxic activity. CD8 T-cell depletion in these models notably reduced vaccine efficacy, underscoring the essential role of these cells. NK cell depletion in untreated models further demonstrated NK cells’ critical function in controlling tumour growth when IL17A was absent. Overall, IL17A depletion enhanced both antigen-specific humoral and cellular immune responses, indicating a shift towards a more robust and responsive immune environment.

Conclusions: Our findings reveal that the absence of IL17A in the pancreatic TME reprograms it into a more immune-supportive environment, favouring the recruitment of effector/memory immune cells upon vaccination. This approach paves the way for novel therapeutic combinations in pancreatic cancer, where IL17A depletion may boost both immunotherapy efficacy and anti-tumour responses.

Background: Alzheimer's disease (AD) is a growing healthcare crisis with limited effective therapies. This study aims to identify new candidate drugs that can be repurposed using key transcriptional regulators (DERs) in AD as therapeutic targets.

Methods: Multi-cohort single-nucleus RNA sequencing (snRNA-seq) data from the prefrontal cortex were analysed to identify DERs. Molecular docking and dynamic simulations analysis evaluated interactions between DERs and 2200 Food and Drug Administration-approved drugs to assess binding stability, whilst pharmacokinetic parameters relevant to blood–brain barrier permeability were evaluated.

Results: We identified 20 key DERs associated with AD. Lasmiditan stood out as the most promising drug amongst other drug candidates (Vorapaxar, Bictegravir, Tonaftate, Fluspirilene, Lisuride, Olaparib) interacting with five DERs: ZEB2, APP, PAX6, ETV6, and ST18. Lasmiditan–ETV6 complex showed the best binding stability (RMSD: 2.98 Å, H-bonds: 68.38) and optimal passive diffusion (LogP3–4, TPSA 60–75 Ų).

Discussion: Lasmiditan is a potential AD therapeutic candidate that warrants further preclinical validation.

Background: Oesophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with limited biomarkers for monitoring tumour burden and prognosis. Circulating tumour DNA (ctDNA) has emerged as a promising tool for real-time disease assessment, but its clinical utility in ESCC remains underexplored.

Methods: In this prospective cohort study, we analysed preoperative and postoperative ctDNA from 54 treatment-naïve ESCC patients undergoing radical surgery using a 61-gene panel. Associations between ctDNA mutations, clinicopathological characteristics and survival outcomes were evaluated.

Results: Preoperative ctDNA mutations were detected in 96.3% of patients (52/54), with Tumour Protein 53 (TP53) (59.3%), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (31.5%) and Phosphatase and Tensin Homologue (PTEN) (13.0%) being most prevalent. Surgical resection significantly reduced ctDNA positivity (p < .0001). Advanced-stage tumours exhibited higher frequencies of PIK3CA (47.8% vs. 19.4%, p = .026) and PTEN mutations (26.1% vs. 3.2%, p = .034). Survival analysis revealed that postoperative TP53 ctDNA positivity predicted worse disease-free survival (DFS; Hazard Ratio (HR) = 3.64, p = .005) and overall survival (OS; HR = 3.29, p = .009), while PIK3CA positivity was associated with improved OS (p = .032). Strikingly, preoperative PTEN ctDNA-positive patients showed dramatically worse outcomes, with median DFS of 4.01 versus 33.27 months (HR = 7.53, p < .001) and OS of 11.80 versus 45.17 months (HR = 5.35, p < .001). In multivariate analysis, preoperative PTEN positivity remained the strongest independent prognostic factor for both DFS (HR = 7.28, p = .002) and OS (HR = 3.76, p = .028), surpassing Tumour, Node, Metastasis (TNM) stage.

Conclusions: Our findings highlight the dynamic role of ctDNA in reflecting ESCC tumour burden and prognosis. While tumour-agnostic ctDNA analysis showed limited clinical utility, gene-specific mutations (TP53, PIK3CA and PTEN) demonstrated significant prognostic value. Preoperative PTEN ctDNA positivity emerged as a robust predictor of aggressive disease, suggesting its potential for risk stratification and personalised therapeutic strategies in ESCC.

Background: Fucosyltransferase 2 (FUT2)-dependent fucosylation of intestinal epithelial cells is vital for preserving gut barrier integrity and microbial balance. Nevertheless, its precise involvement in alcohol-associated liver disease has yet to be fully elucidated.

Methods: We generated mice with intestinal epithelial cell-specific Fut2 knockout (Fut2^△IEC) and established a chronic-binge alcohol model. 16S rRNA sequencing and metabolomics analysis were used to reveal differences in the composition and function of faecal bacteria.

Results: The loss of intestinal epithelial Fut2 exacerbates alcohol-related hepatic oxidative stress damage, and this effect is dependent on gut bacteria. A marked decrease in the abundance of bacteria carrying nicotinamidase (PncA) in the intestines of Fut2^△IEC mice was observed, leading to disrupted nicotinamide metabolism and decreased nicotinic acid production. This reduction in nicotinic acid synthesis results in decreased NAD⁺ production in the liver via the Preiss–Handler pathway. Administering pncA-overexpressing Escherichia coli promotes hepatic NAD⁺ synthesis and alleviates alcohol-related oxidative stress damage in Fut2^△IEC mice.

Conclusion: These findings reveal a gut microbiota–Fut2–pncA axis that modulates alcoholic liver injury in mice, which may offer insights into microbial contributions to alcoholic liver disease in people.

Background: Clinical therapeutic approaches to prevent and treat renal injury in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) induced by calcium oxalate (CaOx) are limited. As a pivotal deacetylase, Sirtuin1 (Sirt1) exhibits notably anti-inflammatory effects, but its metabolic mechanism in regulating CaOx nephropathy remains unexplored.

Methods: We analysed organic acid metabolism in kidney using the nontargeted metabolome and identified key targets by RNA-seq. Evaluate renal injury and oxidative stress using techniques such as Positron Emission Tomography-Computed Tomography (PET/CT) and transmission electron microscope. The protective mechanisms of Sirt1 against CaOx-induced kidney injury and subsequent crystal deposition were demonstrated using in vitro coculture systems and in vivo Sirt1 conditional knockout mice.

Results: We found that Sirt1 has a significant protective effect on renal injury and oxidative stress induced by CaOx. Sirt1 expression decreases in CaOx nephropathy mice, and activation of Sirt1 reduces CaOx-induced kidney injury and crystal deposition by increasing the level of itaconate. In addition, it was found that Sirt1 enhances immunoresponsive gene 1 and inhibits Sdha by trimethylating histones, thereby regulating the oxidation levels of itaconate and succinate. Furthermore, we emphasise the valuable role of Sirt1 agonists and exogenous itaconate in alleviating crystal induced kidney injury.

Conclusions: Our study revealed a previously unknown function of Sirt1 in CaOx nephropathy. By regulating itaconate level through epigenetic, Sirt1 protects against renal inflammation and oxidative damage induced by CaOx. Our preclinical data suggest that targeted Sirt1 agonism represents a promising therapeutic intervention for progressive crystallopathic nephropathy, potentially disrupting the inflammation–crystallisation vicious cycle.

Background: Coronary atherosclerosis (CA) is a leading cause of cardiovascular diseases with the high morbidity and mortality; however, the current diagnostic methods, primarily based on symptoms, signs, lab examination and imaging, are often inadequate for detecting subclinical or early-stage CA, costly, and inaccessible in many cases. The objective of this study was to discover sensitive and specific biomarkers for the diagnosis of CA severity.

Methods: We enrolled 443 participants, including CA patients and healthy controls, from three independent cohorts: discovery, testing, and blinded validation. Multi-omics data integration during the discovery phase identified key features of atherosclerotic progression and potential biomarkers. Biomarker panels were refined using random forest models in the testing cohort, and their performance was evaluated in a blinded validation cohort to assess their ability to monitor the occurrence and development of CA.

Results: Multi-omics analysis revealed that plasma metabolites exhibited the strongest correlation with CA severity, effectively distinguished different CA stages from healthy controls. Post hoc analysis confirmed the diagnostic model's robustness, with an AUC value higher than .933 (95% CI: .828–.984, sensitivity 93.75%, and specificity 80%). In the blinded validation cohort, the biomarker panel achieved AUC values of .821–.898 for CA occurrence and .649–.849 for CA severity. Notably, 90% of these biomarkers remained significant after adjusting for comorbidities (p < .05).

Conclusions: This study identified significant metabolic changes during CA progression and established biomarker panels with potential diagnostic value for assessing CA severity. Key metabolites including cholesteryl sulphate, azelaic acid, tryptophan, arabinofuranosyluracil, TMAO, ADMA, LPC18:2, tartaric acid, L-citrulline, and L-proline, purine, sorbitol, and 2-aminoadipic acid. These findings highlight the potential of these biomarkers to improve early diagnosis and personalised management of CA.

Background: Ulcerative colitis (UC) is an agnogenic chronic intestinal inflammatory disease. Umbilical cord-derived mesenchymal stem cell (UMSC) is a potential therapeutic approach against UC; however, the mechanisms underlying their efficacy for UC remain unclear.

Methods: We performed a single-arm clinical trial with 6 months follow-up to assess the efficacy of UMSC in patients with moderate to severe left-sided UC. The 26 enrolled patients were administered two UMSC doses intravenously. Pre- and post-therapy colon biopsy specimens were analysed by single-cell RNA sequencing (scRNA-seq). Dextran sulphate sodium (DSS)-induced colitis mouse models with or without UMSC injection were used to delineate colon inflammation and T cell function.

Results: In the clinical trial, the clinical response/remission rates were 80.8/46.2% and 75.0/37.5% after 2 and 6 months of therapy, respectively. Endoscopic and histological examinations showed improvement of colonic mucosa after UMSC therapy in responders. scRNA-seq data showed that UMSC therapy may suppress pro-inflammatory features of T lymphocytes and alleviate inflammatory responses by inhibiting the interaction of T cells with B and myeloid cells. In the murine experiment, UMSCs suppressed DUOX2-mediated oxidative stress to attenuate DSS-induced colitis by regulating T cell-mediated immunity.

Conclusion: UMSC therapy primarily modulates T cell-mediated immunity to achieve gut mucosal immune reconstitution and maintain mucosal barrier integrity, thereby achieving effective UC recovery.

Background: Lung cancer, a leading cause of cancer death, displays profound histologic and molecular heterogeneity across adenocarcinoma, squamous, and small-cell types. Clinically, tumours can shift between these states, reflecting lineage plasticity—the reprogramming of differentiated cells to alternate identities. Pre-existing genomic/epigenomic diversity and microenvironmental cues supply the substrates and pressures for plasticity from disease onset. This review anchors plasticity within normal lung development to clarify how fate programs are co-opted to drive progression, immune escape, therapy resistance, and invasion.

Main text: Focusing on the intricate interplay between lineage dysregulation and tumour progression in lung cancer, this review integrates insights from lung tissue development to explore the pivotal molecules and mechanisms driving lineage plasticity, alterations and migration during lung carcinogenesis and progression. Recent research findings on lung cancer lineage plasticity are synthesised, shedding light on the role of transcriptional and epigenetic regulators in disrupting tumour lineages. Particular emphasis is placed on how tumour microenvironmental factors, such as hypoxia, stromal cells and immune cells, reshape tumour cellular profiles by modulating the epigenomic landscape. Furthermore, this review specifically discusses the impact of epidermal growth factor receptor (EGFR) and KRAS mutations on lung cancer progression and the consequent immune escape mechanisms they engender. Importantly, we highlight that lineage regulation persists throughout tumour development, from the early onset of lung adenocarcinoma (LUAD) to its progression through late-stage dedifferentiation and metastasis. We evaluate the implications of these factors on treatment resistance in lung cancer and focus on innovative therapeutic strategies targeting lineage plasticity.

Conclusions: Lineage plasticity spans the entire course of lung cancer, from early tumorigenesis through metastasis to treatment resistance. Lineage transitions that occur during tumour progression arise from specific combinations of genomic and epigenetic alterations and are further shaped by microenvironmental forces such as hypoxia, stromal remodeling, and immune pressure. By summarising current research advancements, we aim to provide new insights for future lung cancer research and to promote the development of more effective therapeutic interventions.