Aberrant deposition of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating β-site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen-activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease-modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease-modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.

Since 2022, mpox epidemics have been sustaining and escalating over the world, posing a significant public health challenge. While significant progress has been made in diagnostic methodologies, prophylactic vaccines, and therapeutic interventions to mitigate monkeypox virus (MPXV) infection, scientific understanding of MPXV and related orthopoxviruses continues to evolve progressively. In order to keep pace with recent advancements, herein we review progress in mpox research from five key perspectives. This article first summarizes the latest epidemiological profiles, incorporating different viral lineages globally and in China, while highlighting their evolutionary history and distinct clinical characteristics. The virological profiles of MPXV shed light on its complete infectious lifecycle and the formation of distinct virus particle types. Clinically approved classical detection methods and emerging novel testing techniques are provided, establishing a framework for early diagnosis of mpox patients. The efficacy and safety of both licensed vaccines and those under development are analyzed to underscore their value in preventing mpox infection. Additionally, progress in approved and newly identified potential therapeutic agents is summarized and discussed, aiming to provide insights for further drug development and clinical treatment strategies.

Myocardial ischemia-reperfusion (MIR) injury is a major cause of cardiac dysfunction, but the spatial heterogeneity of its underlying molecular programs remains unclear. In this study, we applied Visium spatial transcriptomics to generate gene expression maps of rat left ventricles after MIR and identified distinct regional features. The border zones were enriched with phagosome-related genes, incomplete infarct areas showed activation of MAPK, IL-17, and osteoclast differentiation pathways, while the infarct cores were characterized by ferroptosis and mitophagy-related genes. To further resolve the cellular basis, we integrated single-cell RNA sequencing with RCTD deconvolution and found immune cell infiltration in infarct zones, neutrophil enrichment in incomplete infarct areas, and smooth muscle cell predominance in border zones. Both spatial and single-cell analyses revealed altered expression of Piezo1, RyR2, MMP2, and SERCA2, which was further validated by Western blot and immunofluorescence co-staining with ACTN2. Pseudotime analysis demonstrated selective enrichment and dynamic activation of Piezo1 in specific cardiomyocyte subclusters. Functional validation using a hypoxia/reoxygenation model confirmed that reoxygenation induced marked intracellular Ca²⁺ accumulation, which was attenuated by the Piezo1 inhibitor GsMTx4. Together, these findings delineate the spatial heterogeneity of MIR injury, identify Piezo1 as a key mediator of Ca²⁺ dysregulation, and suggest Piezo1 as a potential therapeutic target for myocardial protection.

Macrophages are innate immune cells that extensively infiltrate and play a key role in the tumor microenvironment (TME). Tumor cell–secreted factors recruit monocytes into the TME, where they differentiate into tumor-associated macrophages (TAMs), which can polarize into distinct phenotypes: M1 and M2. M1 TAMs promote antitumor immunity through cytokine secretion and antigen presentation, whereas M2 TAMs support tumor progression by facilitating angiogenesis, invasion, and immune escape. Despite these dual roles, the specific mechanisms governing macrophage plasticity and polarization remain insufficiently understood. This review comprehensively summarizes the origin, polarization, and functional diversity of macrophages in the TME, with emphasis on pathways that regulate TAM-mediated immune responses. Furthermore, this article examines current TAM-targeted therapeutic strategies, including recruitment inhibition, phenotypic reprogramming, and the development of chimeric antigen receptor macrophages (CAR-Ms), as well as macrophage-based drug delivery and exosome therapy. By integrating recent advances in cell engineering and immunometabolism, this review highlights the translational potential of TAM-targeted therapies and their value in reshaping the immunosuppressive TME to enhance cancer immunotherapy.

Sepsis, a life-threatening dysregulated host response to infection, is frequently exacerbated by pyroptosis—a programmed, proinflammatory cell death process mediated by Gasdermin D (GSDMD) activation. Using high-throughput screening, we identified emestrin-type epidithiodiketopiperazines (ETPs) as potent inhibitors of GSDMD cleavage during pyroptosis in Tohoku Hospital Pediatrics-1 (THP-1, a human acute monocytic Leukemia cell line)-derived macrophages. Combined surface plasmon resonance and western blotting analyses demonstrated that these ETPs activate caspase-3/7, which in turn cleaves GSDMD at aspartic acid residue 87 to generate a p10 fragment. This process prevents the formation of the pore-forming p30 fragment, thereby mitigating its associated inflammatory effects. Building on these results, in vivo studies showed that a low dose of the lead emestrin-type ETP (compound 2) protected against lethal lipopolysaccharide (LPS)-induced septic shock and attenuated lung inflammation. This protective effect was further validated in the clinically relevant cecal ligation and puncture (CLP) model, where compound 2 significantly enhanced survival by suppressing the infiltration of GSDMD-positive neutrophils and monocytes. scRNA-seq of murine lung tissue showed that compound 2 suppressed LPS-induced systemic inflammation by inhibiting moDC maturation. Collectively, these findings establish the therapeutic potential of targeting GSDMD-driven pyroptosis with ETPs in sepsis and suggest their promise for clinical translation.

Tuberculosis (TB) remains a major global health challenge. In this study, we applied UPLC-MS/MS lipidomics and data-independent acquisition proteomics to profile plasma from healthy controls, active TB patients, and cured individuals to identify differentially expressed lipids and proteins. Mendelian randomization prioritized phosphatidylcholine (PC) lipids (PC(18:2/18:2), PC(14:0/20:4) and PC(18:0/20:4)) and proteins (haptoglobin [HP], retinol binding protein 4 [RBP4], coagulation factor XIII B subunit [F13B] and inter-alpha-trypsin inhibitor heavy chain 1 [ITIH1]) as candidate diagnostic and cure biomarkers. Binary multi-omics random-forest classifiers constructed with these markers achieved strong diagnostic (AUC = 0.967, 95% CI: 0.928–1.000) and cure-monitoring (AUC = 0.981, 95% CI: 0.956–1.000) performance, which was further assessed with ten-fold cross-validation. Integration with transcriptomic data and lipid-related gene analysis provided additional molecular support for HP. Independent validation in the GSE34608 cohort (AUC = 0.965) and ELISA verification (AUC = 0.969) confirmed HP's diagnostic utility at gene and protein levels. GSVA enrichment implicated HP in iron homeostasis and immune response pathways, suggesting a role in Mycobacterium tuberculosis infection and immune evasion through modulation of host iron metabolism. Overall, we present a robust lipid–protein biomarker panel and accurate multi-omics models for TB diagnosis and monitoring of cure, and propose HP as a promising biomarker and potential therapeutic target. These tools may improve clinical management and treatment evaluation.

Breast cancer is the most common cancer and the leading cause of cancer-related death among women worldwide. Advances in molecular biology, high-throughput sequencing, and integrative-omics have deepened the understanding of its heterogeneity by clarifying mechanisms linked to genetic susceptibility, epigenetic regulation, oncogenic signaling, and immune evasion. Although those developments have driven progress in targeted therapy and screening, concerns on drug resistance, toxicity, global inequities, and suboptimal risk stratification continue to limit outcomes. This review systematically summarizes current advances across four interconnected areas of breast cancer research and management, including molecular pathogenesis, targeted therapy, screening, and prevention. It describes key biological processes that shape tumor heterogeneity and examines targeted therapies, including endocrine agents, HER2-directed drugs, CDK4/6 and PI3K/AKT/mTOR inhibitors, antibody–drug conjugates, and immunotherapies, together with mechanisms of resistance and emerging treatment targets. It also evaluates evolving approaches in risk stratification and screening, highlighting progress in digital breast tomosynthesis, magnetic resonance imaging, contrast-enhanced mammography, and artificial intelligence-assisted interpretation. By integrating cutting-edge molecular insights with clinical advances, this review further highlights the expanding opportunities for personalized therapy and precision prevention. It outlines future directions linking multiomics and artificial intelligence to more equitable and effective breast cancer management.

Immunomodulatory therapies demonstrate variable efficacy in sepsis, suggesting biological heterogeneity inadequately captured by current stratification approaches. Although lymphopenia predicts mortality, functional thresholds and their interaction with inflammation remain poorly characterized. We investigated whether integrating lymphocyte status with systemic inflammation defines sepsis endotypes with differential treatment responsiveness. We retrospectively profiled 714 patients within 24 h using lymphocyte subsets and inflammatory biomarkers. Restricted cubic spline analysis revealed nonlinear associations between lymphocyte counts and mortality (p < 0.01), with steep risk increases at lower counts. Risk optimization identified critical thresholds at 374 cells/µL (total T cells), 340 cells/µL (CD4⁺), and 157 cells/µL (CD8⁺). Principal component analysis of inflammatory markers combined with lymphocyte stratification classified patients into four discrete endotypes with markedly divergent 28-day survival (55%–58% vs. 82–87%, p < 0.001). Patients with immunosuppressed/hypo-inflammatory endotype had higher survival among those who received corticosteroids (CD4⁺-depleted: 84.4% vs. 75.6%, p < 0.001; T-cell-depleted: 78.7% vs. 72.3%, p = 0.006), whereas hyperinflammatory endotypes showed no such association. Integration of publicly available single-cell (GSE167363) and bulk transcriptomics (GSE65682) datasets yielded a 15-gene T-cell dysfunction signature with external validation (CNP0004962, area under the curve [AUC] 0.76–0.85). These observational findings suggest that immune-inflammatory co-profiling identifies biologically distinct sepsis subgroups with differential treatment associations, generating testable hypotheses for prospective validation through endotype-guided trials.

The mechanisms by which muscular dystrophy-related stress is transduced to the autophagic machinery remain poorly characterized. The formulation of strategies should be based on how disruption of these processes results in the deregulation of signaling pathways that contribute to many pathological effects of the disease. In this study, we investigated the molecular mechanism by which the obestatin/GPR39 system, an autocrine signaling with anabolic impact on normal skeletal muscle, restores autophagy in Duchenne muscular dystrophy (DMD). We report that obestatin integrates 5' AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) signaling to control ubiquitin proteasome system (UPS), autophagy–lysosome system, and protein synthesis under dystrophic context. The posttranslational modifications of the E3 ligase NEDD4-L emerges as the main switch to activate the autophagy in response to obestatin. This includes NEDD4-L tyrosine phosphorylation and autoubiquitination, which is critical for recruiting the ubiquitin-specific protease 10 to assemble a deubiquitination complex, that orchestrates the unc-51 like autophagy activating kinase 1 (ULK1) and class III PI3K (VPS34) complexes. Reactivation of autophagy through obestatin signaling promotes the recovery of physiological skeletal muscle function. Thus, DMD conditions determine permissiveness to the activation of AMPK that sustain autophagy under anabolic conditions stablished by obestatin signaling through mTORC1.

Melanoma is the most aggressive skin malignant tumor, typically exhibiting a high mutation burden and potentially harboring mutations in NRAS, BRAF, or NF1. To enhance survival rates, these driver alterations can achieve significant antitumor activity through targeted therapy. In the past decade, BRAF inhibitors combined with MEK inhibitors significantly improved the prognosis of BRAF mutation melanoma. Nevertheless, researchers have attempted various strategies to block the NRAS signaling pathway, NRAS mutation in melanoma is still considered to be untargetable. In recent years, MEK inhibitors like binimetinib and tunlametinib have displayed the efficacy for NRAS^mut melanoma, with tunlametinib being the first and only approved MEK inhibitor for advanced NRAS^mut melanoma. On the other hand, immune checkpoint inhibitors including PD-1/PD-L1 inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors changed the treatment landscape of advanced melanoma. In this review, we have summarized the current knowledge of molecular pathogenesis and classification of melanoma. Subsequently, we explored current and potential treatment approaches for melanoma, primarily encompassing BRAF inhibitors, MEK inhibitors, and immunotherapy, with a particular focus on their clinical relevance of development. Finally, the challenges in the treatment of melanoma, particularly in immunotherapy and targeted therapy, are summarized and discussed.

Organ transplantation has progressed from a life-saving surgical intervention to a multidisciplinary field integrating immunology, bioengineering, and data science. Despite major advances in donor management, perioperative care, and immunosuppression, long-term graft survival remains limited due to chronic rejection, infection, and organ scarcity. Recent breakthroughs in organ preservation, particularly in hypothermic and normothermic machine perfusion, have enabled real-time graft assessment, metabolic reconditioning, and localized therapeutic delivery. Emerging precision immunomodulation strategies, including regulatory T-cell therapy, gene-edited cellular platforms, tolerogenic dendritic cells, and biomarker-guided minimization, are reshaping alloimmune control toward durable tolerance. Innovations in xenotransplantation, multigene-edited donor animals, and tissue biofabrication offer potential solutions to structural organ shortages, although they are accompanied by regulatory and ethical challenges. Artificial intelligence further enhances donor–recipient matching, risk prediction, and personalized immunosuppressive management. This review synthesizes advances in preservation technologies, immune engineering, cellular tolerance induction, artificial intelligence-driven decision support, and xenotransplantation and provides a comprehensive overview of the evolving transplant landscape. By integrating mechanistic insights into translational progress, we outline future pathways for regenerative, immune-educational, and precision organ medicine.

Reproductive toxicity testing is essential for evaluating whether xenobiotics, including pharmaceuticals, environmental chemicals, or ionizing radiation, adversely affect reproductive function. However, conventional assessments rely on mating outcomes or histopathology, which are labor-intensive, variable, and require large numbers of animals. Acrosin, a serine protease encoded by the Acr gene and localized in the acrosome of spermatozoa, plays a critical role in sperm penetration of the zona pellucida. To exploit this germ cell-specific expression, we generated a genetically engineered mouse model in which the Luciferase (Luc) reporter gene is driven by the Acr promoter. This Acr-Luc knock-in (KI) model enables longitudinal and quantitative imaging of spermatogenesis using bioluminescence. We demonstrate that this platform captures radiation-induced impairments in male fertility in real time, eliminating the need for terminal analyses. By allowing repeated evaluation within the same individuals, our approach reduces interindividual variability and enables a substantial reduction in animal use, aligning with the “Reduction” principle of the 3Rs. Moreover, it reveals both the onset and recovery phases of spermatogenic disruption with high temporal resolution. The Acr-Luc KI model provides a reliable preclinical platform for reproductive toxicity testing and offers broad utility for studies in reproductive biology, toxicology, and oncofertility research.

This study explored the microevolution of Shigella sonnei in China, focusing on 281 isolates exhibiting coresistance to ceftriaxone and azithromycin (cef^R azi^R) and 99 ONPG-negative isolates. Phylogenetic analysis revealed that waterborne outbreak strains, characterized by multidrug resistance (MDR) and cef^R azi^R, clustered within the predominant domestic lineage I. In contrast, sporadic MDR strains harboring a wider array of antimicrobial resistance (AMR) genes were primarily associated with lineage II. The cef^R azi^R phenotype in lineage I was mediated by an IncB/O/K/Z plasmid carrying bla_CTX-M-14, mphA, aac(3)-IId, dfrA17, aadA5, and sul1 genes. Lineage II strains acquired cef^R azi^R through a distinct IncFII plasmid possessing bla_CTX-M-15, ermB, and mphA genes, and additionally carried a separate IncB/O/K/Z plasmid backbone with bla_TEM-1, dfrA12, sul2, strA, strB, tet(A), and aac(3)-IId genes. Conversion to the ONPG-negative phenotype was linked to a deletion spanning approximately 10 kbp, which included two insertion sequences (IS1 and IS600), the mhpBAR operon, and the lacIZY operon. Genomic comparisons identified 66 SNPs and 9 accessory genes correlated with lineage II, and 23 SNPs with 9 accessory genes associated with ONPG-negative variants. Ongoing surveillance of S. sonnei epidemic clones is essential to elucidate their microevolution, track transmission, and assess public health implications.

Hepatocellular carcinoma (HCC) was characterized by a highly complex genome, with structural variations (SVs) playing a significant role in its development. In this study, we employed Oxford Nanopore Technology long-read sequencing in paired tumor and adjacent normal liver tissues from 74 Chinese HCC patients to thoroughly characterize the landscape of somatic SVs. Our analysis revealed that somatic SVs were more prevalent in hepatitis B virus (HBV)-related HCC, with chromosome 1 emerging as a major hotspot, and several members of the chromosome 1 open reading frame (C1orf) family genes expression level exhibited significant age-related difference. Notably, HBV-related HCC cases exhibited a higher frequency of deletions, particularly among younger ones (≤ 35 years old). In addition, we observed an increased burden of HBV integration events in younger ones. Remarkably, the divergent-paired related homeobox (DPRX) loci was identified as a novel gene for HBV integration in younger patients. Together, these findings delineated the somatic SV landscape in HCC and underscored age-associated HBV-related genomic alterations as key pathological features of hepatocarcinogenesis.

Organoid technology has become among the most popular technologies in recent years, due to their three-dimensional and physiologically enriching models that closely mimic the structure and function of human organs. Herein, this review details the in-depth methodology, updated to date, for the efficient cultivation of organoids. Emphasizing liver organoids, both hepatocyte and cholangiocyte derived, and other abdominal organ systems, such as gut, kidney, and pancreas, we explore the technological challenges researchers are facing nowadays, including how to optimize nutrient delivery, maintain cellular diversity, achieve scalability in the organoid culture system, and high-throughput applications. Addressing those biological and technological complexities, this review aimed at equipping new researchers with practical insights and standardized protocols that will help improve reproducibility and success rates in organoid culture and expand their applications. Furthermore, we discuss current limitations and barriers to clinical translation, highlight key knowledge gaps, and outline emerging innovations, including bioengineering, microfluidic systems, and genetic manipulation, expected to further enhance disease modeling, personalized medicine, and regenerative therapies. Finally, we provide perspective on next-generation technologies that expedite organoid-based discovery and development.

Ischemic heart disease is one of the diseases with the highest morbidity and mortality in the world. The N⁷ -methylguanosine (m⁷ G) tRNA modifications are widely recognized as one of the most prevalent tRNA modifications. Nevertheless, there is still a lack of understanding regarding the roles and molecular mechanisms underlying the METTL1-mediated m⁷ G tRNA modification in cardiac ischemia/reperfusion (I/R) injury. METTL1 and m⁷ G tRNA modification were upregulated in mice with I/R injury hearts and the plasma of patients with acute myocardial infarction. Thus, we constructed METTL1 knockout mice and found that silencing METTL1 alleviates I/R. Mechanistically, tRNA sequencing, MeRIP-m⁷ G-tRNA sequencing, and Ribosome profiling sequencing were used to clarify deficiency of METTL1 reduced the levels of m⁷ G tRNA modifications and m⁷ G-modified tRNAs, and consequently, downregulated the translation efficiency of ATPIF1 mRNA to restore the level of mitochondrial oxidative phosphorylation and suppress the increase of mitochondrial apoptosis. Moreover, cardiac-specific overexpression of ATPIF1 induced myocardial hypertrophy and inhibited the protective effect of silencing METTL1 on cardiac I/R injury. Collectively, m⁷ G tRNA modifications regulate the translation efficiency of ATPIF1, which eventually mediates mitochondrial energy metabolism, apoptosis, and myocardial I/R injury. The findings uncover that interfering with METTL1 and ATPIF1 represents a novel therapeutic target in myocardial I/R injury.

Cancer and tissue regeneration pose great challenges to global health, as cancer treatment is impeded by tumor heterogeneity and therapy resistance, while regenerative medicine is constrained by donor shortages and difficulties in replicating native tissue structures. Organoids, as advanced three-dimensional multicellular structures derived from stem cells, have emerged as transformative tools in biomedical research. They recapitulate key aspects of native human tissue composition and functions, offering enhanced physiological relevance over traditional models. Therefore, this review aims to highlight the latest advancements in organoid technology within the fields of cancer research and regenerative medicine. We begin by discussing the fundamental aspects of organoid generation, characterization, and application. Furthermore, recent progress in both cancer-oriented and regeneration-focused organoids is summarized, with an emphasis on their applications in disease modeling, drug screening, mechanistic analysis, and precision medicine. Based on an extensive review of the literature, the current challenges and future directions in the development and application of organoid models are discussed. As organoid technology continues to evolve, it is anticipated that more high-quality studies will further advance medical science and foster innovation in personalized therapeutics.

The clinical utility of mesenchymal stem cells (MSCs) is often limited by pulmonary entrapment and poor systemic distribution, particularly in diseases constrained by physiological barriers such as rheumatoid arthritis (RA), where joint accessibility restricts therapeutic efficacy. This study systematically compares the immunomodulatory capacity and inflammation-targeting potential of human gingiva-derived MSCs (GMSCs) and their extracellular vesicles (GMSC-EVs) in vivo. Using an experimental RA model, we demonstrate that GMSC-EVs exhibit superior tropism to inflamed joints compared to GMSCs, resulting in significantly greater amelioration of disease severity, including reduced joint swelling, bone destruction, and balanced pathogenic T-cell responses. Mechanistically, we identify C-C chemokine receptor type 2 (CCR2) as the critical molecular driver of this targeted homing. Genetic ablation of CCR2 via CRISPR-Cas9/sgRNA knockdown abolishes both the joint-specific accumulation of GMSC-EVs and their therapeutic efficacy. These findings elucidate the molecular basis for GMSC-EVs tropism to arthritic lesions and establish CCR2 as a pivotal target for developing precision-engineered EVs therapies with enhanced specificity for RA treatment.

The involvement of circular RNAs (circRNAs) have been well-documented in various cancers, including hepatocellular carcinoma (HCC); however, their regulatory roles in HIF-1α-mediated tumorigenesis remain largely unclear. This study elucidates the functional significance of N6-methyladenosine (m6A)-modified circRNA—circIST1 in HCC progression. Elevated expression of circIST1 was observed in both HCC clinical specimens and cultured cell lines. This pronounced upregulation was found to be associated with poor prognosis and survival. Functionally, circIST1 drives HCC progression by enhancing tumor cell proliferation, migration, and invasion and by inhibiting apoptosis, as validated in vitro and in vivo. Mechanistically, it functions as a competitive endogenous RNA (ceRNA) that sponges miR-140-3p and miR-182, thereby relieving their repression on the common downstream oncogene, HIF-1α. Rescue experiments confirm that the tumor-suppressive effects of circIST1 silencing are reversed upon inhibition of these miRNAs or overexpression of HIF-1α. Notably, we show that circIST1 drives HIF-1α-mediated aerobic glycolysis—a metabolic hallmark of cancer—-by enhancing glucose uptake, lactate production, and glycolytic flux. Furthermore, we identify methyltransferase-like 3 (METTL3)-dependent m6A modification as a critical regulator of circIST1 stability. Collectively, our findings uncover a novel m6A-circIST1-miR-140-3p/miR-182-HIF-1α regulatory axis that underlies metabolic reprogramming in HCC, positioning circIST1 as a promising therapeutic target for HCC metabolic intervention.

The Wnt signaling pathway deeply participates in multiple physiological and pathological processes. Its activity is intricately regulated by a diverse network of modulators, reflecting the pathway's structural and functional complexity. Dysregulation of Wnt signaling leads to cellular dysfunction and is associated with a wide spectrum of diseases, among which tissue fibrosis represents a major pathological outcome, characterized by activation of myofibroblasts and subsequent excessive deposition of extracellular matrix in response to injury. Wnt signaling is a central driver of fibrotic progression across multiple tissues and organs; however, effective therapeutic strategies directly targeting Wnt signaling in fibrosis remain scarce. In this review, we provide a comprehensive overview of Wnt pathway components, regulatory mechanisms, and therapeutic approaches. We systematically examine how Wnt signaling governs both developmental processes and pathological conditions, with particular emphasis on its role in fibrosis while also extending discussion to other diseases. Special attention is devoted to the secreted frizzled-related proteins (SFRPs) family, soluble regulators with biphasic, context-dependent effects that are especially relevant in fibrosis. Finally, we summarize insights from preclinical and clinical studies, review advances and challenges in the development of small-molecule compounds targeting Wnt components, highlighting the vital role of SFRPs as promising targets for antifibrotic intervention.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs and involving both innate and adaptive immunity. Dendritic cells (DCs) play a crucial role in linking innate and adaptive immune responses, and therefore they deeply participate in the initiation and development of SLE. Deleted in breast cancer-1 (DBC1) is a negative regulator of deacetylase SIRT1 (the mammalian homolog of silent information regulator 1) and involves in tissue inflammation. Roles of DBC1 in immune cells remain largely unknown, especially in DCs. We here identified that DBC1 is upregulated in activated DCs, and DBC1 deficiency weakened DC maturation while promoting B7-H1 expression. DC conditional knockout of DBC1 ameliorated murine lupus pathology by decreasing autoantibodies, complement C3, plasma cells, and follicular T helper (Tfh) cells, whereas promoting regulatory T-cell development. We further demonstrated that Dbc1^-/- DC lowered proinflammatory cytokine secretion such as IL-4, IL-6, and IL-12, and reduced signal transducer and activator of transcription 5 (STAT5) signal. With STAT5 overexpression, the protective effect by Dbc1^-/- DC was abolished in the lupus model. Therefore, targeting the DBC1-STAT5 axis in DCs diversifies the therapeutic strategies for SLE.

Neoadjuvant therapies incorporating immune checkpoint inhibitors (ICIs) have shown promise in locally advanced head and neck squamous cell carcinoma (HNSCC). However, biomarkers for pathological complete response (pCR) remain undefined. In the CheckRad-CD8 trial (NCT03426657), we performed RNA sequencing on pre- and post-treatment biopsies from 77 locally advanced HNSCC patients treated with induction chemoimmunotherapy. Of these, 42 patients achieved pCR, while 35 had residual disease (RD). Differentially expressed genes (DEGs) and pathways were identified using DESeq2 and gene set enrichment analysis. Tumor immune microenvironment analysis, utilizing eight RNAseq deconvolution methods, assessed 266 gene signatures and 38 curated immunotherapy signatures. Baseline intratumoral CD8+ T-cell density, stromal tumor lymphocyte infiltration, and combined PD-L1 proportion score were associated with pCR. Pretreatment analysis identified 830 DEGs between pCR and RD, with T and B-cell-related pathways enriched in pCR samples. Logistic regression models indicated the significance of T and B cells and IFN-gamma signaling in predicting pCR. Furthermore, a new CheckRad-7-gene signature, with an AUC of 0.902 in the training cohort, effectively predicted pCR and survival, serving as a robust biomarker for prognosis and treatment response in HNSCC.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related deaths worldwide, characterized by genomic heterogeneity arising from ethnic and interindividual differences. Producing region-specific data to characterize ethnic-specific somatic mutations is essential for advancing CRC research. Additionally, accurate somatic mutation detection requires paired tissue analyses to account for interindividual diversity. This study aims to highlight the importance of ethnic diversity in shaping CRC's genomic landscape and emphasize the necessity for region-specific data to refine diagnostic and therapeutic approaches. This study emphasizes the need for region-specific data by analyzing an unprecedented 197 paired samples from the Korean CRC cohort through whole-genome sequencing. We identified 78 potential driver genes. Notably, CBWD5, LRRIQ3, TRIM64B, SPINK5, and ZNRF2 were linked to recurrence, presenting potential therapeutic targets. Our analysis revealed 30 mutational hotspots, with significant variants in KRAS (25%, G12A, G12D, G12V), MAP1A (12%, V2300G), and TP53 (8%, R175H). We identified a significant co-occurrence between KRAS 12 mutation and PIK3CA 545 mutation. Our findings demonstrate potential driver genes and mutational hotspots associated with CRC patient, characterizing the mutational landscape related to clinical characteristics. Significantly advancing our understanding of CRC's heterogeneous nature, this study lays a solid foundation for devising more efficacious management strategies.