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Lactate, an energy source and metabolic by-product, has been implicated in cancer progression, but its role in colorectal cancer (CRC) remains incompletely understood. This study investigated the clinical significance, biological effects, and transcriptomic responses of CRC cells to lactate. In human CRC specimens, lactate levels were positively associated with advanced clinical stage and poorer disease-free survival. Functional assays showed that lactate promoted malignant cellular behaviors in both SW480 and HCT116 cells, while pH-control experiments suggested that these effects were not merely due to extracellular acidification alone. RNA sequencing in SW480 cells identified 1,418 differentially expressed genes after lactate treatment. GO and KEGG analyses revealed alterations in multiple metabolic and signaling pathways. qRT-PCR validated the alterations of representative genes, including HK2, VEGFA, JUNB, CCNB1, MAPK4, and COX2. In addition, flow cytometry showed activation of NF-κB and HIF-1α signaling following lactate treatment, and pharmacological inhibition of either pathway significantly attenuated the lactate-induced malignant phenotypes. Together, these findings provide transcriptomic and functional evidence that lactate promotes malignant phenotypes in CRC cells and offer exploratory mechanistic insights into the involvement of NF-κB and HIF-1α signaling.

In this review we comprehensively discuss organic cation transporter novel 1 (OCTN1), encoded by the SLC22A4 gene as a member in the solute carrier 22 (SLC22) family, which facilitates the cellular transport of diverse cationic and zwitterionic substrates. OCTN1 is highly expressed in many vital organs in humans, where it facilitates absorption and distribution of both endogenous compounds and therapeutic drugs. Among its substrates, ergothioneine (EGT) serves as the primary antioxidant and anti-inflammatory molecule, underscoring the essential role of OCTN1 in cellular defense and inflammation control. Genetic polymorphisms in SLC22A4 significantly alter OCTN1 expression, substrate affinity, and drug pharmacokinetics, with strong associations to susceptibility and treatment outcomes in human diseases. Insights from knockout models revealed that OCTN1 deficiency leads to reduced EGT availability, heightened oxidative stress, and aggravated inflammation, particularly in the tissues such as intestine, liver and lung. Moreover, OCTN1 activity is dynamically regulated by epigenetic modifications, cytokines, and hormones, linking it to immune modulation and disease progression. Put together, OCTN1 plays a defined role via high-affinity EGT transport, while its broader transport capacity and pharmacological relevance remain under investigation, with possible - though not yet established - implications for inflammation-associated biomarker development.

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism presenting with acute liver failure, cirrhosis, or neurologic involvement. Liver transplantation (LT) is the definitive treatment; however, data remain limited, particularly from regions reliant on living donor LT (LDLT). We retrospectively analyzed a prospectively collected transplant database, identifying all patients (≥ 14 years) who underwent LT for WD between January 2001 and December 2023. Data on demographics, LT indications, disease characteristics, pre-transplant therapy, complications, and outcomes were collected. Survival was assessed using Kaplan-Meier methods, and neurologic outcomes from clinical documentation. Forty-one patients underwent LT for WD (median age: 23 years; 51.2% female). Ascites was present in 68.4%, encephalopathy in 32.4%, and hepatocellular carcinoma in 5.1%. Acute liver failure was the initial presentation in 17.9%. LDLT comprised 53.7%. Acute cellular rejection occurred in 29.7% but was manageable; no patient required re-transplantation. Neurologic involvement was present in 17.1%, with 71% improving post-LT. One-, five-, and ten-year survival rates were 94%, 94%, and 82%. LT for WD yields excellent long-term survival. Neurologic improvement occurred in most Neuro-Wilson patients, supporting LT even in neurologically affected cases. LDLT plays a crucial role in regions with limited deceased donors.

Itch is a complex noxious sensation associated with many skin and systemic conditions, which varies in intensity and quality across different body regions. Despite its prevalence, the molecular and cellular mechanisms underlying regional itch differences remain poorly understood. Investigating the neural basis of regional itch differences, we identified a functional divergence in neuropeptide signaling and central circuit engagement between the trigeminal and spinal systems, which was independent of peripheral innervation density. Utilizing a combination of behavioral, pharmacological, genetic, and molecular assays, we identified a unique population of trigeminal (TG) neurons that facilitate specialized itch-pain coding. Our results indicate that while histamine receptors HRH1 and HRH3 are both involved in mediating mixed itch-and-pain sensations, the specific activity of Substance P (SP)- and Somatostatin (SST)-expressing neurons orchestrates this transition in the cheek. This behavioral shift is mediated by a central mechanism wherein sensory neurons activation recruits distinct nociceptive circuits within the brainstem. In brief, these findings provide insights into the molecular and cellular mechanisms underlying regional itch differences, highlighting the importance of considering anatomical location when developing targeted treatments.

Visual impairment affects over 2.2 billion people worldwide and the major causes include age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy. For research in these areas, although animal models offer a more physiologically complex system than in vitro approaches, their use raises ethical considerations, and species-specific differences such as variations in protein sequences and signaling pathways. This can limit the direct translatability of the outcomes. Traditional 2-D cell cultures, in contrast, lack the multicellular organization and dynamic microenvironment necessary to replicate human retinal complexity. Retinal organoids (ROs), three-dimensional tissue constructs derived from pluripotent stem cells, have emerged as a promising model due to their human origin and complex cellular interactions that cannot be achieved in conventional 2-D/3-D co-culture models. In this review, we provide a brief overview of the evolution from 2-D to 3-D retinal models, highlight the structural and functional features of ROs including the presence of layered retinal architecture, photoreceptor outer segment formation, and light-responsive electrophysiological activity and summarize their applications in disease modeling, drug discovery, and gene and cell therapy. ROs represent a significant advancement over traditional models by enabling the recapitulation of human-specific retinal development, facilitating the study of patient-derived disease phenotypes, and providing a platform for personalized therapeutic screening. Their development has deepened understanding of pathological mechanisms in conditions such as retinitis pigmentosa and AMD, while enabling preclinical testing of targeted interventions like CRISPR-based gene editing and photoreceptor cell replacement. Nonetheless, challenges remain in fully replicating retinal vascularization, long-term functional maturation, and synaptic connectivity, underscoring the need for continued refinement and integration with complementary model systems.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors composed of cells exhibiting an epithelioid morphology. These cells typically arrange around small blood vessels (perivascular spaces) and display dual differentiation characteristics of smooth muscle cells and melanocytes. Diagnosis is challenging due to the absence of specific symptoms or tumor markers. This case features a young male patient with a large hepatic PEComa, whose imaging findings resemble those of hepatocellular carcinoma. We have detailed the entire process from diagnosis to treatment to aid in differential diagnosis and surgical planning. A 31-year-old male patient with no prior medical history underwent a routine health examination 20 days prior to presentation. Although the patient was asymptomatic, ultrasound revealed an incidental hepatic lesion measuring 58 × 50 × 45 mm (maximum diameter 58 mm, or 5.8 cm). The screening center suspected a hemangioma. Subsequently, he presented to our hospital. Comprehensive imaging studies, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), revealed a 58 mm-diameter space-occupying lesion in segments V and VIII of the right hepatic lobe. Imaging findings initially raised suspicion for hepatocellular carcinoma. To minimize surgical trauma and preserve liver function, our team discussed surgical approaches and ultimately decided on a laparoscopic partial hepatectomy. During the procedure, we obtained a specimen for pathological examination. The final histopathological analysis confirmed the diagnosis of a PEComa with undetermined malignant potential. The patient recovered smoothly postoperatively and was successfully discharged. PEComa has an insidious onset and is rare. Early diagnosis is often challenging, and imaging studies typically show no highly specific findings. Clinical diagnosis frequently relies on biopsy. In terms of treatment, radical resection (R0 resection, i.e., negative margins) represents the definitive therapeutic approach.

Fuchs endothelial corneal dystrophy (FECD) is a progressive degenerative disease of the corneal endothelium and remains a leading indication for corneal transplantation worldwide. FECD is characterized by excessive extracellular matrix (ECM) deposition, disruption of proteostasis with endoplasmic reticulum (ER) stress, and progressive endothelial cell loss; however, no pharmacological therapy is currently available. Given that FECD involves multiple interacting pathogenic pathways, we asked whether a structure-based polypharmacology approach could identify a single small molecule capable of modulating distinct disease-relevant targets. We performed virtual screening of 1,178 FDA-approved compounds against transforming growth factor-β receptor type II (TGF-βR2) and p38 mitogen-activated protein kinase (p38 MAPK), which contribute to ECM dysregulation and stress-induced apoptosis. VX-809 was the only compound predicted to bind both targets, with docking scores of - 8.5 kcal/mol for TGF-βR2 and - 10.7 kcal/mol for p38 MAPK; molecular dynamics simulations further supported stable protein-ligand interactions. In patient-derived FECD corneal endothelial cells, VX-809 attenuated TGF-β2-induced apoptosis, suppressed activation of Smad2/3 and p38 MAPK signaling, and reduced ECM overproduction and global protein synthesis. VX-809 also decreased aggresome formation and dampened activation of the PERK, IRE1α, and ATF6 arms of the unfolded protein response, consistent with improved protein homeostasis under stress conditions. Together, these findings show that structure-based screening can reveal previously unrecognized multi-target activities in existing drugs and identify candidate modulators of converging pathogenic pathways in FECD. This study provides proof of concept for docking-based polypharmacology strategies to accelerate early-stage discovery for multifactorial ocular diseases.

Patients with Down Syndrome (DS) are characterized by dysfunction of several organs, including the liver, brain, heart defects, gastrointestinal anomalies, and lethal immune hypersensitivity. A person with DS is also susceptible to various inflammatory diseases, including hepatic autoimmune diseases. The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is known to trigger the stimulator of interferon genes (STING) and downstream proinflammatory factors. In this work, we hypothesized that oxidative stress-associated DNA damage triggers activation of the cGAS-STING signaling pathway and promotes liver inflammation in DS. Here, we investigated the role of reactive oxygen species (ROS) associated DNA damage and the cGAS-STING signaling pathway in the pathogenesis of hepatic inflammation in the DS model. Our results showed that DS cells harbor excessive ROS and DNA damage in DS fibroblasts and DS mouse liver. Further, DS cells accumulate micronuclei that likely serve as a source of cytoplasmic DNA to stimulate cGAS-STING activation. In addition, RNA-seq analysis results showed enhanced expression of key type I interferon factors in cGAS-STING pathways in DS liver and inflammatory responses and elevated liver enzymes such as alanine transaminase (ALT) that indicate a hepatocellular liver injury in DS. The results of this study opened the opportunity to connect endogenous DNA damage triggers innate immune response, which may contribute to the upregulation of the cGAS-STING signaling to exacerbate hepatic inflammation in DS.

Feedforward loops (FFLs) and feedback loops (FBLs) are ubiquitous network motifs that mediate signal filtering, pulse generation, and state switching; yet, how coupling FBLs to FFLs produces robust multistability-a key mechanism for cellular decision-making-remains unclear. Here, we systematically investigate coupled FFL-FBL architectures by focusing on two prevalent FFL types, each with AND or OR logic, yielding four distinct frameworks. For each framework, we enumerate all 36 = 729 possible circuits, corresponding to three possible states (activation, inhibition, or absence) for each of six feedback edges, formulate each circuit as a system of ordinary differential equations, and quantify robustness as the proportion of 100,000 randomly sampled parameter sets exhibiting multistability. Our results reveal two key principles. First, positive self-activation is a primary driver of multistability, but the identity of the critical node(s) depends on the FFL type and logic. Second, coherent FFLs support multistability more readily than incoherent ones, whereas the choice between AND and OR logic has a comparatively weaker effect. Notably, we identify representative high-performing circuits within each framework and find that a small set of circuit designs remain robustly multistable across all four frameworks. These findings advance the theoretical understanding of motif design and provide practical guidelines for engineering synthetic multistable circuits.

IL-11, a novel target for drug development, has been associated with several fibroinflammatory diseases including thyroid eye disease (TED), where it plays an important role in signaling to stromal cells activating multiple intracellular pathways. In TED patient tissue, IL-11 is elevated and stimulates multiple effects important in disease progression, including the production of proinflammatory cytokines, hyaluronic acid (HA) and fibrotic markers. LASN01, a potent antibody to IL-11 receptor, inhibits these effects and is a potential therapeutic agent for TED. Teprotumumab, an antibody to IGF-1 receptor, inhibits HA production and adipogenesis and is effective in reduction of proptosis. Activation of the IGF-1 and IL-11 pathways in TED tissue induces the expression of fibroinflammatory genes regulated by LASN01 and lipid biosynthetic genes regulated by Teprotumumab. Clinical studies show that LASN01 is well tolerated and in a placebo-controlled phase II trial in TED, LASN01 resulted in a statistically significant resolution of clinical activity score (CAS) in 88% of treated patients (p = 0.028), but had lesser effects on proptosis. The data supports the importance of IL-11 biology in fibroinflammatory disease and that IL-11 receptor is a pharmacologically active target for drug development.

Vaults are massive ribonucleoprotein complexes, highly conserved and abundant in eukaryotic cells, yet with unclear function. Their thin-walled barrel-shape architecture is composed of two symmetrical, antiparallel half-shells, each containing 39 copies of the major vault protein (MVP). The spacious lumen of the vault suggests a role in cellular transport. Although vaults are thought to undergo conformational changes to facilitate cargo exchange, the molecular basis for their inherent flexibility remains unknown. Here, we integrate cryogenic electron microscopy (cryo-EM) and multi-scale molecular dynamics (MD) simulations to reveal the structural determinants of the human vault particle's flexibility. Cryo-EM identified two high-resolution alternative conformational states: a symmetric and an asymmetric structure, pointing to the vault shell's structural plasticity. MD simulations of these conformations revealed that these structures are flexible and exhibit breathing-like motions, and porous solvent-exposed surfaces. Mutagenesis disrupting persistent MD-identified inter-half contacts reduced full MVP shell assembly, confirming the functional relevance of these flexibility determinants. Together, these findings establish the molecular basis for the human vault particle's conformational plasticity.

Gastric cancer (GC) poses a significant health threat, and alterations in Fatty acid β-oxidation (FAO) may influence its progression. However, the precise mechanisms underlying this association remain unclear. FAO-related genes were analyzed using transcriptomic datasets from databases of GEO and TCGA. Totally 160 FAO-associated genes were identified, and a risk scoring model was subsequently established to stratify patients into groups of low- and high-risk. Immune characteristics, drug sensitivities, and hub genes, including IL-6, were assessed. Subsequently, immunoblotting and immunohistochemistry were performed on GC cell lines and tissue samples to evaluate IL-6 expression. Analysis of the TCGA and GEO databases revealed a FAO-related gene signature comprising ACADS, ACO2, CPT2, SLC22A5, AOC3, CD36, CIDEA, G0S2, GABARAPL1, and SERINC1. We also examined gene mutations and constructed a prognostic risk scoring model with validation achieved through a nomogram to predict gastric cancer risk. Immune infiltration analysis and drug sensitivity testing (e.g. AG-014699, Axitinib, BX-795, and Cisplatin) were also conducted. IL-6 emerged as a core gene with significant expression difference across cellular and tissue levels. FAO plays a critical role in the prognosis of GC, and IL-6 may serve as a key biomarker for diagnosis and therapeutic strategies.

Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.

Plant cells are connected to their neighbors via plasmodesmata facilitating the exchange of nutrients and signaling molecules. During immune responses, plasmodesmata close, but how this contributes towards a full immune response is unknown. To investigate this, we develop two transgenic lines which allow to induce plasmodesmal closure independently of immune elicitors, using the over-active CALLOSE SYNTHASE3 allele icals3m and the C-terminus of PDLP1 to drive callose deposition at plasmodesmata. Induction of plasmodesmal closure increases the expression of stress responsive genes, salicylic acid accumulation and resistance to Pseudomonas syringae DC3000. More homogeneous plasmodesmal closure using icals3m also leads to the accumulation of starch and sugars, decreases leaf growth, as well as hypersusceptibility to Botrytis cinerea. Based on the profile of responses, we conclude that plasmodesmal closure activates stress signaling, raising questions about the signals mediating this response and whether these responses occur in all circumstances when plasmodesmata close.

GDP-Mannose transporters are Golgi-localised solute carriers that are essential for the virulence of pathogenic fungi, serving as critical components of fungal glycosylation pathways. However, the mechanism by which nucleotide sugars are recognised and transported across the Golgi membrane remains unclear, hindering efforts to develop effective inhibitors that could serve as distinct antifungal agents. Here, we present cryo-EM structures of the GDP-Mannose transporter, Vrg4, from Candida albicans in complex with nanobodies in both the cytoplasmic and Golgi-facing states. Structural comparisons between these two states, in addition to a GDP-mannose bound structure, demonstrate the importance of ligand movement during transport. Additionally, we demonstrate the ability of the nanobodies to specifically inhibit Vrg4, presenting proof-of-principle that nanobodies can be used as effective inhibitors of nucleotide sugar transport and glycosylation in cells.