Cholelithiasis represents a common clinical condition within the digestive tract and continues to pose a substantial global health challenge, largely due to its high rate of recurrence and a scarcity of effective non-surgical interventions. Although protein succinylation has been widely characterized as a post-translational modification, its implications in cholelithiasis pathogenesis had remained poorly defined. A groundbreaking study by Wang et al demonstrates that lysine acetyltransferase 2A-mediated succinylation of adenosine monophosphate-activated protein kinase suppresses cholelithiasis. This work not only provides novel mechanistic insights into cholelithiasis but also establishes succinylation as a promising therapeutic target, thereby addressing a critical knowledge gap in the field.

Small-molecule drug discovery targeting the orphan G protein-coupled receptor GPR84 as potential therapeutics.

Caspase-1, a cysteinyl aspartate-specific protease central to inflammasome activation, acts as a master regulator of multiple programmed cell death (PCD) pathways including pyroptosis, apoptosis, necroptosis, ferroptosis, and PANoptosis. It interacts with other caspases and is tightly modulated by epigenetic mechanisms and post-translational modifications. During the tumor microenvironment and immune metabolic regulation, it is activated and acts in a context-dependent way. Given this multifaceted involvement in cancer, neurodegenerative diseases and autoimmune disorders, caspase-1 represents a promising yet challenging therapeutic target. Despite extensive research, challenges persist in the insufficient understanding of crossover mechanisms and research of caspase-1 inhibitors. This review systematically clarifies its paradoxical roles by integrating caspase-1' s regulatory and context-dependent networks across PCD, epigenetics, tumor microenvironment, immune metabolism, and diverse diseases. Additionally, we summarize therapeutic progress and root causes of caspase-1 inhibitors' clinical failure as well as putting forward some innovative treatment strategies, aiming to offer new perspectives for future treating design.

ALB suppresses epithelial-mesenchymal transition and glycolysis via SPARC regulation in metastatic clear cell renal cell carcinoma.

Progressive myoclonus epilepsy EPM1 is a rare neurodegenerative disease caused by partial loss of function of cystatin B (CSTB), a cysteine protease inhibitor with known neuroprotective roles. The disease mechanisms remain largely unsolved, and no treatments are available to control the debilitating myoclonus in EPM1. We investigated the impact of CSTB loss on transcriptome and proteome in three regions of CSTB-deficient (Cstb-/-) mouse brain - the cerebellum, cerebral cortex, and hippocampus - during disease progression, providing comprehensive insights into the molecular changes and disease mechanisms. We elucidated three critical pathways as potential therapeutic targets. First, a significant upregulation of immune response genes indicates heightened immune activity across all brain regions. Second, a consistent downregulation of the oxidative phosphorylation pathway with differential expression of mitochondrial genes implies impaired energy metabolism primarily affecting the cerebellum. Third, an upregulation of genes essential for lysosomal function with simultaneous downregulation of genes encoding proteins crucial for lysosomal acidification suggests lysosomal dysfunction as an essential pathogenetic mechanism. By combining proteome with transcriptome data, we identified clusterin, apolipoprotein E, peroxiredoxin 6, cathepsin D, and aldolase C as potential biomarkers for disease progression.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by endothelial dysfunction, vascular remodeling, and a sustained increase in pulmonary vascular resistance, causing cardiopulmonary damage. The apelin receptor (APJ), a member of the G protein-coupled receptor family, has emerged as an essential modulator of vascular homeostasis. Clinical and preclinical studies have demonstrated that its activation exerts beneficial effects on the progression of PAH. Its main actions include the restoration of endothelial function, reactivation of the BMPR2/SMAD axis, induction of nitric oxide-mediated vasodilation, inhibition of autophagy and the migration of the pulmonary artery smooth muscle cells (PASMCs). Furthermore, its expression and functionality are modulated by epitranscriptomic mechanisms, particularly by microRNAs involved in the post-transcriptional regulation of key genes for vascular homeostasis. These findings position the APJ as a relevant therapeutic target in PAH. However, the clinical application of its agonists still faces pharmacokinetic limitations that restrict their therapeutic use. Therefore, the aim of this review is to gather current information on APJ in the pathophysiology of PAH and focus attention on its potential as a therapeutic target.

IL-23 as a potential mediator of immune evasion and therapeutic target in laryngeal squamous cell carcinoma.

Epigenetic silencing of tumor suppressor genes is a hallmark of cancer progression. The FXYD (FXYD domain-containing ion transport regulator) family, classically known for ion transport regulation, has recently been implicated in oncogenesis; however, the role of its founding member, FXYD1, in breast cancer remains unclear. Here, FXYD1 is identified as a significantly downregulated gene in breast cancer tissues, and low FXYD1 expression is associated with unfavorable patient prognosis. Integrative transcriptomic, clinical, and epigenetic analyses revealed that promoter hypermethylation drives FXYD1 silencing. Functional restoration of FXYD1 suppressed cell proliferation, migration, and lung metastasis both in vitro and in vivo. Mechanistically, FXYD1 acts as a nuclear scaffold that recruits the E3 ubiquitin ligase MAEA to the RNA helicase DDX5, a coactivator of β-catenin, promoting K63-linked ubiquitination and proteasomal degradation of DDX5. This process reduces β-catenin stability, impairs its nuclear translocation, and attenuates Wnt target gene expression. Collectively, our findings uncover a previously unrecognized FXYD1-MAEA-DDX5 axis that inhibits Wnt/β-catenin signaling through a non-canonical ubiquitin-proteasome pathway, establishing FXYD1 as a tumor suppressor and potential prognostic biomarker and therapeutic target in breast cancer.

Identification of the disulfidptosis-related gene G6PD as a potential biomarker and therapeutic target in pancreatic ductal adenocarcinoma by integrative bioinformatics analysis and experimental validation.

DKC1: a robust prognostic factor and potential therapeutic target in multiple myeloma.

Contezolid is a novel oxazolidinone antibiotic for the treatment of gram-positive bacteria, which are one of the most common pathogens of pneumonia. We conducted a prospective, single-center, open-label study to evaluate the clinical and microbiological efficacy, safety profile, and pulmonary epithelial lining fluid (ELF) penetration characteristics of contezolid in adult pneumonia patients. Sparse blood samples and bronchoalveolar lavage fluid samples were collected from patients after multiple oral doses of 800 mg of contezolid twice a day. Pharmacokinetic parameters were calculated by developing population pharmacokinetic (PopPK) modeling, and probability of target attainment was evaluated by Monte Carlo simulations. The study enrolled 15 patients (mean age 55 years) with primarily community-acquired pneumonia. Contezolid achieved a clinical cure rate of 80.0% and a bacterial clearance rate of 71.4%. Oral contezolid was well tolerated, and no drug-related adverse effects were observed in any of the subjects. The mean area under the concentration-time curve (AUC₀-₁₂,ss) was estimated by the PopPK model to be 33.06 mg·h/L in ELF and 71.95 mg·h/L in plasma. Assuming a plasma protein binding rate of 90% based on literature data, the ELF-to-free plasma AUC0-12,ss ratio was 4.50. When the minimum inhibitory concentration was ≤4 mg/L, 800 mg of contezolid q12h could achieve the optimal therapeutic target in the plasma of patients with pneumonia. This study demonstrates that contezolid achieved excellent pulmonary penetration in adult patients with pneumonia.

Background/Objectives: Hepatic encephalopathy (HE) is characterized by hyperammonemia, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) dysfunction, with brain endothelial cells being highly vulnerable to ammonia-induced damage. Adiponectin is a cytoprotective adipokine that may enhance endothelial resilience; however, its specific role under hyperammonemic conditions remains unclear. This study aims to investigate the protective effects of adiponectin on brain endothelial function and BBB integrity. Methods: In vivo, male C57BL/6J mice underwent bile duct ligation (BDL) surgery and received daily intraperitoneal adiponectin injections (10 μg/kg/day) for 6 days, starting 5 days post-surgery. On day 11, brain tissues and serum were collected for molecular and cytokine analyses. In vitro, mouse brain endothelial cells (bEnd.3) were pretreated with adiponectin before exposure to ammonia. Assays for tight junction preservation, mitochondrial membrane potential, reactive oxygen species (ROS) generation, and total RNA sequencing were performed. Results: In BDL mice, adiponectin increased the expression of the tight junction protein claudin-5 and synaptic marker PSD95 across the cortex, hippocampus, and striatum, while reducing pro-oxidant (Cyp2e1, Cyp4a1) and apoptotic (Caspase-9) markers. In vitro, adiponectin pretreatment maintained tight junction proteins, suppressed inflammatory markers, restored mitochondrial membrane potential, and decreased ROS generation in ammonia-exposed bEnd.3 cells. Transcriptomic profiling revealed that adiponectin modulates stress-related gene expression under hyperammonemic conditions. Conclusions: Adiponectin enhances cellular stress resistance and maintains BBB structural integrity under ammonia-induced toxicity. These findings suggest that adiponectin serves as a promising therapeutic target for mitigating neurovascular unit dysfunction in hepatic encephalopathy.

This study aimed to investigate the role of CXCL9 during titanium implant osseointegration. Lentivirus-mediated overexpression and knockdown models of Cxcl9 were used in male C57BL/6 mice. Titanium implants were placed in the maxillae of the mice, and the osseointegration process was analyzed using micro-CT to evaluate bone volume and mineral density, histological staining to visualize bone-to-implant contact (BIC), RT-qPCR to detect osteogenic gene expressions, and enzyme-linked immunosorbent assay to assess inflammatory cytokine levels. Results showed that Cxcl9 overexpression significantly impaired osseointegration, as evidenced by reduction in bone volume, bone mineral density, and BIC. This was accompanied by an increase in osteoclast numbers. Moreover, Cxcl9 overexpression suppressed expression of osteogenic genes and resulted in elevated pro-inflammatory cytokines, including TNFα and IL1β. Conversely, Cxcl9 knockdown improved osseointegration, suggesting that CXCL9 is a negative regulator of bone remodeling at implant sites. Further, CXCL9 expression impairs titanium implant osseointegration. This highlights CXCL9 as a potential therapeutic target to improve dental implant osseointegration, particularly in patients with inflammatory conditions.

Proteostasis is the finely tuned balance of protein synthesis, folding and degradation essential for cellular health. When this equilibrium is disrupted, misfolded proteins accumulate, triggering adaptive stress responses such as the unfolded protein response and the integrated stress response (ISR). Central to the ISR is the kinase GCN2, a sensor of amino acid deprivation and ribosomal stress. Upon activation, GCN2 phosphorylates eIF2α, dampening global translation while selectively enhancing the synthesis of the stress-responsive transcription factors ATF4 and CHOP. ATF4 orchestrates a broad transcriptional programme that supports amino acid metabolism, redox homeostasis, autophagy and proteasomal degradation, which are key processes for restoring proteostasis. Beyond its canonical role, GCN2 interfaces with other regulatory networks modulating mTORC1 to promote autophagic clearance of damaged proteins and organelles, facilitating stress granule formation, and integrating signals from oxidative and endoplasmic reticulum stress to rebalance the proteome. Dysregulated GCN2 activity has been implicated in diverse pathologies including neurodegeneration, cancer and pulmonary vascular disease, positioning it as a promising therapeutic target. In this review, we explore how GCN2 links nutrient sensing to translational control and metabolic adaptation, and how its central role in proteostasis may inform new strategies for treating diseases driven by protein misfolding and stress pathway imbalance.

The efficacy of combined chemotherapy and programmed cell death protein-1 (PD-1) immune checkpoint blockade (ICB) is constrained by the collateral cytotoxicity of chemotherapy toward proliferating tumor-specific CD8+ T (TTST) cells, a population indispensable for antitumor immunity. This study aimed to overcome this limitation by targeting a potential chemotherapy-resistant immune cell reservoir. By using the murine acutely resolved lymphocytic choriomeningitis virus (LCMV) infection and tumor models (colorectal cancer and melanoma), we characterized the susceptibility of CD8+ TTST and virus-specific bystander memory CD8+ T (TBYS) cells to platinum-based chemotherapy-induced cytotoxicity. We next evaluated the antitumor efficacy and underlying mechanisms of combined chemotherapy and TBYS cell-targeted oncolytic virus therapy (OV-BYTE) in tumor-bearing mice with prior LCMV infection or SARS-CoV-2 vaccination. Finally, we assessed the antitumor efficacy of the triple combination regimen (including OV-BYTE, chemotherapy, and PD-1 ICB) in both murine colorectal cancer model and patient-derived colorectal cancer organoid. We first demonstrated that within the tumor microenvironment, CD8+ TTST cells are highly susceptible to platinum-based chemotherapy, whereas CD8+ TBYS cells constitute a quiescent, chemo-resistant population. Leveraging this, CD8+ TBYS-targeted OV-BYTE therapy synergized with chemotherapy to control tumorigenesis in multiple murine models. Mechanistically, this dual combination directly engaged the CD8+ TBYS cell reservoir for tumor killing, which was accompanied by the restoration of CD8+ TTST cell function via reduced apoptotic susceptibility and acquisition of a polyfunctional, effector-like state. Consequently, integrating OV-BYTE into the standard chemo-PD-1 ICB regimen resulted in improved antitumor efficacy in both preclinical and patient-derived tumor models. Our study establishes the chemotherapy-resistant CD8+ TBYS cell niche as a pivotal therapeutic target. By engaging this target, OV-BYTE emerges as a potent combinatorial agent that successfully circumvents a core limitation of standard chemo-immunotherapy, thus offering a rationally designed and translatable strategy to advance combination cancer therapy.

Hepatocellular carcinoma (HCC) is a highly aggressive primary liver malignancy characterized by limited therapeutic options and poor prognosis. Within the tumor microenvironment (TME), tumor-associated macrophages (TAMs) predominantly exhibit an M2-like phenotype, contributing to immune escape and tumor progression. Zymogen granule protein 16 (ZG16) has been reported to be downregulated in HCC, but its precise biological function and molecular mechanisms remain poorly understood. Therefore, we aimed to investigate the impact of ZG16 on HCC cell metastasis and TAM infiltration, as well as to elucidate its molecular mechanism. Gain- and loss-of-function assays were used to verify the effect of ZG16 on HCC cell metastasis, as well as the recruitment and M2 polarization of TAMs. The underlying mechanism of ZG16 was explored by immunoprecipitation-liquid chromatography-mass spectrometry (IP-LC/MS) analysis, co-immunoprecipitation (co-IP) assay, and GST pull-down assay. Our results demonstrated that ZG16 overexpression significantly inhibited metastasis of HCC cells while also suppressing the recruitment and M2 polarization of TAMs, suggesting its dual role in both tumor cell-intrinsic and microenvironmental regulation. Notably, sorting nexin 9 (SNX9), a facilitator of HCC, was identified as a downstream target of ZG16. Mechanistically, we uncovered that ZG16 physically interacted with SNX9 and promoted its protein degradation through the ubiquitin-proteasome pathway. Functional rescue experiments provided compelling evidence that SNX9 overexpression effectively counteracted ZG16-mediated suppression of both HCC progression and TAM M2 polarization. Further mechanism exploration confirmed that ZG16 promoted the ubiquitination and degradation of SNX9 by recruiting itchy E3 ubiquitin protein ligase (ITCH). Our findings certify that ZG16 suppresses tumor progression and M2 polarization of TAMs in HCC through ITCH-mediated ubiquitination and subsequent degradation of SNX9. The ZG16/ITCH/SNX9 axis may represent an important regulatory pathway and potential therapeutic target for HCC.

This review summarizes the critical role of the Notch signaling pathway in cardiac development, congenital heart disease, and myocardial regeneration. The Notch signaling pathway exerts a profound impact on cardiac health and disease progression by finely regulating the fate determination of cardiac progenitor cells, cardiac morphogenesis, and the proliferation and apoptosis of cardiomyocytes. The article also explores the research progress of the Notch signaling pathway as a potential therapeutic target and looks forward to future research directions.

Oncostatin M (OSM) has been shown to contribute to metabolic dysfunction-associated steatohepatitis (MASH) progression to hepatocellular carcinoma (HCC). Here we investigated its role in shaping an immunosuppressive tumor microenvironment (TIME) in MASH-HCCs. OSM role was investigated through combined analyses of MASLD/MASH patients with or without HCC, MASH-related HCCs originating in wild type and hepatocyte-specific OSM receptor-β (hOSMRβ-/-) deficient mice and in vitro experiments performed on liver cancer and immune cell lines. Analysis of OSM-expressing HCC patients with mixed etiology (TCGA-database) revealed a positive correlation between OSM transcripts and those of several TIME markers. A similar pattern was also observed in murine MASH-HCC tumors. hOSMRβ-/- mice had significantly reduced tumor volume and weight without altering macrophage infiltration and OSM production. However, TIME markers transcripts were lower in HCCs from hOSMRβ-/- mice. These effects associated with a lowering in tumor STAT3 phosphorylation and COX-2 activity. Single-cell RNAseq analysis of human HCCs identified malignant hepatocyte as source of CCL15, a cytokine associated with immunosuppression in HCCs. Circulating CCL15 was markedly elevated in either human and rodent MASH-HCCs and significantly reduced by hOSMRβ deletion. Blocking autocrine OSM signaling in HepG2 or Huh7 cells overexpressing OSM reduced STAT3 phosphorylation, CCL15 production and prevented TIME markers expression by co-cultured macrophage-derived THP1 cells. Our findings provide compelling evidence for an autocrine role of OSM/OSMRβ axis in promoting CCL15 production by tumor cells which, in turn, stimulates an immunosuppressive TIME in MASH-HCCs, suggesting OSM as a potential therapeutic target for HCC treatment.

Abstract Targeted electrical approaches to the treatment for Parkinson’s disease (PD) include deep brain stimulation (DBS), which is effective for core motor symptoms, such as essential tremor. Interestingly, treating comorbid depressive symptoms in PD, using electroconvulsive therapy (ECT), also appears to help motor disability. But it is unclear whether such electrical strategies have any impact on the underlying disease processes of PD. Since aggregation of misfolded alpha-synuclein fibrils is a pathological hallmark of PD, this may be an important therapeutic target. To this end, we presently assessed whether direct current stimulation (DCS) of cortical neurons that were seeded with wild-type or A53T alpha-synuclein mutant pre-formed fibrils (PFFs) would reduce their aggregation. We found that both wild-type and A53T alpha-synuclein PFFs readily induced alpha-synuclein aggregation in primary cortical neurons and this effect was more pronounced at embryonic day 17 (E17), compared to less mature E14 derived neurons. We did find that DCS time-dependently reduced alpha-synuclein accumulation (phosphorylated and aggregate forms) within neurons and increased neuronal viability. Increased extracellular alpha-synuclein levels suggest that the DCS induced an increase in neuronal activity causing the clearance of the intra-cellular alpha-synuclein. These data have implications for non-invasive neuromodulation strategies to lower alpha-synuclein burden and possibly correct aberrant neuronal firing in PD and other alpha-synucleopathies.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder predominantly affecting individuals over 60. Its motor symptoms stem from the deterioration of dopaminergic neurons within the substantia nigra. Despite aging being a significant risk factor, the specific mechanisms linking aging and PD pathology remain unclear. Leveraging advancements in single-cell genomics, this study utilizes single-nucleus multiome sequencing to capture transcriptomic and epigenetic profiles from 40,125 cells across the lifespan of the mouse substantia nigra. Our analysis pinpoints age-associated changes at a cell type-specific level, revealing a subset of genes that increasingly express with age and are enriched in PD-related pathways, notably in oligodendrocytes at late aging stages. Integration with five public PD single-cell RNA-seq datasets highlights 85 genes consistently differentially expressed with aging and PD. Key genes such as Hsp90aa1 and Hsp90ab1 are upregulated at late aging stages in oligodendrocytes, microglia, and glutamatergic neurons. Additionally, Apoe in microglia and genes related to protein folding in oligodendrocytes are upregulated at late aging stages, while genes involved in myelination are downregulated at early aging stages in oligodendrocyte. Our multiomic atlas underscores the substantial regulatory network changes during aging that may predispose to PD, providing valuable insights for furthering understanding of PD pathogenesis and potential therapeutic targets.