Understanding the ultrastructural basis of nano-biointerface interactions is crucial for clarifying the mechanisms by which cells recognize, internalize, and react to nanoscale systems. Natural extracellular vesicles (EVs), synthetic nanocarriers including liposomes and dendrimersomes, as well as nanofibrous scaffolds, all interact with cellular membranes through nanoscale mechanisms that regulate cell morphology, signaling, and structural remodeling. EVs possess biologically evolved membrane protein signatures and lipid compositions that facilitate receptor-mediated binding, membrane fusion, and selective internalization. By contrast, synthetic nanovesicles mimic these behaviors through engineered bilayer composition, surface functionalization, and tunable deformability, while nanofibrous scaffolds modulate cell adhesion and cytoskeletal alignment through topographical guidance cues rather than biochemical recognition. Vesicular nanosystems mainly drive curvature-dependent membrane remodeling (wrapping/endocytosis), whereas nanofibrous scaffolds primarily act through integrin clustering and focal-adhesion mechanotransduction; these distinct processes can converge on shared outcomes such as cytoskeletal reorganization and signaling. High-resolution imaging techniques have been critical in visualizing these processes and uncovering nanoscale heterogeneity in vesicle morphology, membrane thickness, and cytoskeletal organization. Emerging correlative methods combining live-cell imaging with electron microscopy further improve mechanistic understanding of dynamic vesicle-membrane interactions and nano-induced structural transitions. Despite these advances, significant knowledge gaps remain, including real-time visualization of membrane deformation and quantitative models linking nanomaterial stiffness to specific uptake pathways. By integrating natural and synthetic nanosystems within a unified ultrastructural framework, this review advances mechanistic understanding of nano-biointerface dynamics and provides structural guidelines for designing next-generation bioinspired materials with predictable cellular interactions.

Neurodegeneration in Alzheimer's disease (AD) remains an unmet therapeutic challenge. Brain delivery of promising agents such as Brilliant Blue G (BBG), a selective P2X7 receptor antagonist, is limited. This study aimed to develop and optimize mucoadhesive chitosan-coated spanlastic nanovesicles (Ct-SNVs) for efficient nose-to-brain delivery of BBG. SNVs were prepared by thin-film hydration and coated with chitosan via electrostatic adsorption. A 23 factorial design optimized the coating process to minimize drug loss and vesicle size while maximizing zeta potential. The optimized formulation yielded nanosized, positively charged vesicles with high encapsulation efficiency; DSC and FTIR of the BBG-Ct-SNVs showed the absence of the drug's crystalline thermal and spectral signatures, indicating its molecularly dispersed state within the vesicles. The coated system provided diffusion-controlled sustained release, strong mucoadhesion, and superior ex vivo nasal permeation and mucosal retention compared with uncoated SNVs. In vivo, BBG-Ct-SNVs increased peak brain concentrations by approximately twofold and enhanced targeting parameters, while sustaining drug levels for 24 h compared with the uncoated formulation. Molecular readouts showed that AlCl3 increased P2X7R expression. It activated both the NLRP3 inflammasome (elevated NLRP3, caspase-1 activity, IL-1(3, and IL-18) and the cGAS-STING pathway (upregulated cGAS and STING mRNA; increased phosphorylated STING, TBK1, and IRF3), leading to induction of IFN-(3 and CXCL10. BBG-Ct-SNVs suppressed these signals more effectively than free BBG or uncoated SNVs. They also reduced cortical oxidative stress and A(31-42 burden. This study provides the first in vivo evidence in an AD-like context that intranasal BBG delivered via mucoadhesive spanlastic nanovesicles suppresses cGAS-STING signaling.

Ovarian cancer (OC) is still one of the most serious gynecologic malignancies in the world. It is characterized by a significant likelihood of recurrence and resistance to conventional therapies and a lack of efficient screening techniques. MicroRNAs (miRNAs) are small, noncoding RNA molecules that exert pivotal functions in modulating gene expression. miRNAs are improperly regulated in OC, contributing to tumor onset, progression, metastasis, and resistance to chemotherapeutics. As a result, miRNAs are promising therapeutic targets for the treatment of OC. Recently, natural products derived from plants and other sources have drawn more interest because of their potential to modulate miRNA expression. A variety of bioactive substances, such as curcumin, quercetin, and others, have shown the ability to either promote tumor-suppressing miRNAs or suppress tumor-promoting miRNAs. These substances have a great deal of promise for improving the effectiveness of traditional chemotherapy, lowering adverse effects, and providing more individualized treatment plans. Additionally, their capacity to target several miRNAs implicated in cancer-related pathways offers a multimodal strategy for treating OC. We can upgrade the potential therapeutic options for OC and other cancers by exploring novel natural products with miRNA-modulating effects. However, further research is needed to clinically translate miRNA-based therapeutics employing natural compounds, especially in the areas of safety, bioavailability, and drug delivery methods. This review emphasized the implications of miRNAs in OC, the impact of natural products on miRNA regulations, and the potential for incorporating these natural substances into clinical practice for individualized and successful OC treatments.

Cardiovascular diseases (CVDs) continue to be the world's leading cause of death, driven by intricate processes such as inflammation, endothelial dysfunction, oxidative stress, and apoptosis. MicroRNAs (miRNAs), small non-coding RNAs that influence mRNA translation, have become recognized as key regulators of these harmful mechanisms in conditions like heart attack, heart failure, and atherosclerosis. Because they remain stable in the bloodstream, miRNAs hold promise as convenient, minimally invasive biomarkers for early CVD detection, assessing risk, and forecasting outcomes. On the treatment side, targeting miRNAs offers a way to correct disrupted molecular pathways with precision, though moving this approach into clinical use presents hurdles such as refining delivery methods, avoiding unintended effects, and achieving specificity for certain tissues. Current studies emphasize progress in understanding how miRNAs contribute to CVD development and their emerging potential in personalized care. Yet, translating these findings into routine practice will require overcoming technical challenges and establishing consistent standards. This evolving area holds great potential to transform cardiovascular medicine through precise diagnostics and targeted therapies, potentially addressing current shortcomings in treatment effectiveness.

Steatohepatitis integrates metabolic stress and mitochondrial damage, but single-node interventions often incompletely quell inflammation and fibrosis. We tested a dual-node strategy that reduces the trigger and blocks the adaptor of the mtDNA-cGAS-STING pathway in a high-fat diet plus streptozotocin mouse model. Male C57BL/6 J mice with steatohepatitis (SH) received urolithin A (UA; mitophagy enhancer), C176 (murine STING inhibitor), or their combination. Endpoints included liver injury (ALT/AST), lipids (serum and hepatic triglycerides, cholesterol), glycemia/insulin resistance (fasting glucose, insulin, HOMA-IR), cGAS-STING/type-I interferon signaling (Ifnb1, Cxcl10, IFN-β, CXCL10; p-STING, p-TBK1, p-IRF3), mitochondrial damage signals (cytosolic mtDNA, mtTFA), autophagy/mitophagy (LC3-II/I, cleaved-PINK1, p-PARKIN, p62), inflammasome/cytokines (NLRP3, IL-1β, TNF-α), and fibrosis (hydroxyproline, Col1a1, Tgfb1/TGF-β1). Compared with SH, UA or C176 monotherapy improved injury, lipid, interferon, and fibrotic readouts, with UA preferentially lowering mtDNA/mtTFA and C176 more strongly suppressing p-STING-TBK1-IRF3 and IFN-β/CXCL10. The combination produced the largest, pathway-concordant effects across domains, frequently approaching CTRL. Formal combination analysis on fractional inhibition showed predominant synergistic activity (ΔBliss and ΔHSA > 0 for most endpoints). A precision-weighted correlation map linked insulin resistance, mitochondrial stress, cGAS-STING activation, and fibrosis, while mitophagy restoration markers correlated inversely. By pairing a mitophagy enhancer with a STING inhibitor, we provide first evidence in this model that coordinated upstream and downstream targeting of the mtDNA-cGAS-STING axis yields superior, multi-domain control of disease biology and is immediately translatable via IFN-β/CXCL10, cell-free mtDNA, and imaging readouts.

Ulcerative colitis involves epithelial injury, crypt distortion, barrier failure, and inflammatory activation within colonic tissue. To support local delivery of the P2X7R antagonist Coomassie Brilliant Blue G-250 (BBG), we developed lactose-decorated, alginate-coated chitosan nanoparticles (ALG-BBG-LCS NPs) and evaluated whether this dual-modified polysaccharide carrier could decouple colonic exposure from systemic exposure while translating into structural protection in dextran sodium sulfate-induced colitis. Lactosylated chitosan was synthesized by the Maillard reaction and confirmed by 1H NMR, FTIR, and substitution-degree analysis. BBG-loaded nanoparticles were prepared by ionic gelation, coated with alginate, and characterized for size, surface charge, entrapment-efficiency, morphology, and pH-sequential release. ALG-BBG-LCS NPs formed spherical nanoparticles (255.16 ± 2.75 nm) with negative surface charge (-22.1 ± 1.31 mV), entrapment-efficiency of 76.57 ± 0.48%, and markedly reduced pre-colonic BBG release. In colitic rats, the optimized formulation produced the highest colonic exposure with the lowest systemic exposure, highlighting the ability of this dual-modified nanocarrier to preferentially localize BBG to the diseased colon while limiting off-target distribution. More importantly, it attenuated disease activity and preserved tissue organization, as shown by improved macroscopic appearance, reduced histologic injury, lower nuclear phospho-NF-κB p65 immunostaining, and restoration of ZO-1 and Occludin expression. These structural improvements were accompanied by suppression of the colonic P2X7R/NF-κB/NLRP3/caspase-1 axis, reduced cytokine and oxidative injury, and improved barrier-function indices. Overall, ALG-BBG-LCS NPs provide a colon-directed BBG platform whose significance extends beyond drug delivery to decoupling colonic drug exposure from systemic exposure and thereby promoting preservation of colonic tissue architecture and epithelial barrier integrity in experimental colitis.

Hypertension is increasingly recognized, especially in vascular remodeling and target-organ injury, as elevated arterial pressure accompanied by chronic low-grade vascular inflammation. Endothelial dysfunction, vascular smooth muscle cell remodeling, immune activation, oxidative stress, and extracellular matrix stiffening reinforce one another in hypertensive vascular disease. The NLRP3 inflammasome is an important mediator of sterile inflammation through caspase-1 activation, IL-1β/IL-18 maturation, and gasdermin D-dependent pyroptosis. Although canonical biochemical triggers of NLRP3 are well characterized, the contribution of the hypertensive mechanical environment remains incompletely defined. Hypertensive vessels are exposed to elevated circumferential stretch, disturbed shear stress, pulse-related strain, and matrix stiffening, which are sensed through integrins, focal adhesions, mechanosensitive ion channels, junctional complexes, and cytoskeletal networks. Direct vascular evidence, indirect mechanobiology evidence, and inflammasome cell-biology evidence are consistent with a testable mechanical licensing model of NLRP3 activation in hypertensive vasculature. In this model, chronic mechanical load may prime vascular cells through integrin-FAK/Src-RhoA/ROCK, Piezo1-Ca2 + , YAP/TAZ, ROS, and NF-κB-associated pathways, while cytoskeletal remodeling could create intracellular conditions that favor NLRP3-ASC proximity and caspase-1 activation in the presence of canonical triggers. Mechanical inputs are not substitutes for canonical danger signals; instead, they may lower the activation threshold for inflammasome assembly, cytokine release, endothelial dysfunction, and vascular remodeling. Mechanotransduction, cytoskeletal remodeling, and inflammasome signaling therefore may represent convergent mechanistic nodes in hypertensive vascular inflammation.

Lupus nephritis (LN) is initiated by immune-complex deposition, complement activation, and inflammation, but these mechanisms do not fully explain why some glomerular lesions resolve whereas others progress to podocyte depletion, glomerulosclerosis, and fibrosis. We present a conceptual spatial framework in which graded disruption of the podocyte organelle-contact network may contribute to this transition. The framework does not assume that contact-site abundance is uniformly protective or injurious. Contactome remodeling denotes an axis-specific change in contact distance, length, frequency, molecular composition, or organelle positioning, whereas contactome collapse is reserved for a composite state in which abnormalities across multiple contact axes are accompanied by concordant calcium, bioenergetic, redox, degradative, or cytoskeletal failure. Mitochondrial fragmentation, lysosomal redistribution, or urinary mitochondrial and podocyte-derived markers alone do not establish contactome collapse. Direct population-level three-dimensional mapping of podocyte contact sites in human LN biopsies is not yet available; therefore, the model remains a proposed organizing framework rather than an established human disease mechanism. The framework predicts that integrated contact-site metrics should provide information beyond isolated mitochondrial, autophagy, or cytoskeletal markers, precede established podocyte detachment, and improve risk prediction only after adjustment for histologic class, activity and chronicity, proteinuria, kidney function, treatment exposure, and competing kidney injury. These predictions can be tested and refuted through standardized human-biopsy morphometry, longitudinal LN models, perturbation-rescue experiments, and biopsy-linked biomarker cohorts.

Lytic cell death has long been interpreted as a terminal consequence of inflammasome activation, gasdermin cleavage, and osmotic membrane failure. Recent evidence supports a more differentiated cellular model in which early membrane permeabilization and terminal plasma membrane rupture are distinct events. However, these processes are still frequently treated as a single continuum, and a unifying framework that separates and integrates them across lytic death pathways is lacking. Within this revised framework, ninjurin 1 (NINJ1) has emerged as the best-supported mediator of plasma membrane rupture during terminal lytic cell death. Studies in pyroptosis, post-apoptotic lysis, ferroptosis, and related necrotic settings indicate that NINJ1 is not required for inflammasome assembly, gasdermin processing, or early cytokine release, but is crucial for terminal membrane disruption and release of large intracellular contents. Structural, biochemical, and imaging data further show that NINJ1 transitions from an autoinhibited membrane-associated state to higher order assemblies that destabilize or excise plasma membrane regions. These findings support a staged model of lytic death in which gasdermin pores establish a permeabilized state, whereas NINJ1 drives the final disintegration of the cell surface. Across these contexts, NINJ1 is best viewed as a convergent membrane-rupture effector that defines a distinct downstream layer of lytic cell death rather than a pathway-restricted component. This distinction has important implications for understanding how membrane rupture shapes cell morphology, extracellular release patterns, and tissue injury. By integrating evidence across lytic death programs, this review advances a unified framework in which permeabilization and terminal rupture are mechanistically separable, differentially regulated processes.

Epstein-Barr virus (EBV) is a complex human herpesvirus characterized by a protein core, a 162-capsomer nucleocapsid, and a glycoprotein-spiked envelope, which facilitates its transmission through bodily fluids. The virus primarily targets B cells and oropharyngeal epithelial cells, establishing infection through viral gp350/220 binds to the host CD21/CR2 receptor, followed by gp42 interacting with HLA class II molecules to trigger endocytosis. Once infection is established, EBV utilizes two main types of encoded microRNAs to regulate the host environment. The BHRF1 miRNAs are expressed early to promote rapid cell proliferation and prevent B-lymphocyte apoptosis by targeting pro-apoptotic proteins. Meanwhile, the BART miRNA cluster, including miR-BART1, miR-BART2, miR-BART3, miR-BART4, miR-BART7, miR-BART8, and miR-BART22, which are robustly expressed in epithelial malignancies like nasopharyngeal and gastric carcinomas, has been found to significantly suppress caspase-3, a central executioner of apoptosis and target host immune mediators like CXCL-11 to stifle antiviral responses. Moreover, Min et al. discovered that miR-BART1-3p inhibited the expression of Disabled homolog 2 (DAB2), a tumor suppressor gene linked to apoptosis, in EBVaGC cells, allowing them to evade programmed cell death. EBV’s ability to cycle between B cells and epithelial cells, along with its association with the modulation of host cell processes and immune responses, highlights the mechanisms by which EBV establishes infection and contributes to oncogenesis.

Angiogenesis, which is the formation of new blood vessels from existing vasculature, exhibits a pivotal role in breast cancer progression and promotes metastasis. This complex biological process is influenced by the dynamic balance of pro- and anti-angiogenic factors within the tumor microenvironment, such as vascular endothelial growth factor, fibroblast growth factors, and angiopoietins. Targeted therapeutic strategies have been developed to interfere with angiogenic signaling, aiming to normalize or inhibit the tumor vasculature. In recent years, miRNAs have arisen as crucial post-transcriptional regulators of gene expression implicated in angiogenic homeostasis. These microRNAs can function as either promoters or suppressors of angiogenesis by targeting mRNAs that encode angiogenic factors or other signaling molecules. Deregulated expressions of these miRNAs in BC are associated with perturbed angiogenesis, tumor progression, and therapeutic resistance. This review presents a thorough overview of the molecular processes controlling angiogenesis in BC and highlights the emerging roles of angioregulatory miRNAs. The article also discusses the therapeutic potential of targeting miRNAs to modulate tumor angiogenesis, providing novel insights for the development of miRNA-based diagnostics and therapeutics in BC management.

Steatohepatitis links cholesterol-crystal injury to ATP-gated purinergic signaling, culminating in NF-κB/NLRP3 inflammasome activation and metabolic dysfunction. We posited that dissolving cholesterol burden while concurrently blocking P2X7 would reprogram lysosomal-purinergic crosstalk and outperform single-pathway therapy. In a streptozotocin-high-fat-diet diabetic rat model, hydroxypropyl-β-cyclodextrin (HPβCD; cholesterol efflux/crystal dissolution) combined with the P2X7 antagonist coomassie brilliant blue G-250 (CBB) improved glucose tolerance, fasting glycemia, and HOMA-IR beyond either monotherapy. In addition, this dual intervention lowered transaminases and inflammatory cytokines; reduced hepatic fibrosis and lipid overload; and restored lysosomal and insulin-signaling readouts. Mechanistically, dual treatment most effectively suppressed the P2X7-Panx1 axis, restored lysosomal integrity (increased LAMP1, decreased cathepsin-B), and curtailed NF-κB/NLRP3-GSDMD signaling, indicating disruption of the feed-forward loop connecting lysosomal injury with purinergic activation. Synergy at fixed in-vivo doses was formally quantified by HSA and Bliss, with the largest Bliss gains at purinergic-inflammasome nodes (P27RX, Panx1, NLRP3, p-AKT/AKT) and coherent effects at lysosomal biogenesis markers (LAMP1, TFEB). Integrative network analysis intersecting cholesterol-regulated genes with the P2RX7 interactome revealed an overlap enriched for IL-1β processing, pyroptosis, and lysosomal organization, nominating a high-connectivity P2RX7/Panx1-LAMP1/CTSB-NLRP3 module selectively reprogrammed by the combination. This work provides in-vivo evidence that simultaneously targeting cholesterol-crystal-driven lysosomal injury and ATP-gated P2X7 signaling yields mechanistic and therapeutic synergy, while linking systems-level network topology to multi-arm pharmacodynamics to define a reprogrammable lysosomal-purinergic module. Collectively, the data establish a mechanistically anchored, clinically plausible combination strategy for diabetes-associated steatohepatitis that surpasses single-pathway interventions.

Kaposi sarcoma (KS) is a vascular malignancy caused by human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV). Clinically, KS presents with characteristic lesions on the skin or mucosal surfaces and may extend to internal organs, leading to serious complications such as gastrointestinal bleeding and lymphedema. The prevalence of KSHV varies markedly by geography, with the highest rates reported in sub-Saharan Africa, the Mediterranean region, and high-risk populations such as individuals living with HIV/AIDS. KS pathogenesis is primarily driven by KSHV-induced cellular transformation, persistent inflammation, and angiogenesis, regulated by viral proteins and microRNAs (miRNAs). miRNAs, as key post-transcriptional gene regulators, play dual roles in cancer progression, acting as either oncogenes (oncomiRs) or tumor suppressors. In KS, oncogenic miRNAs such as KSHV-encoded miR-K12-11 and miR-K12-1 promote tumorigenesis by inhibiting tumor-suppressor pathways and activating signaling cascades, including NF-κB/IL-6/STAT3. Conversely, tumor-suppressor miRNAs such as miR-34a, Let-7, and miR-126 are often downregulated, enabling uncontrolled cell proliferation, angiogenesis, and immune evasion. Emerging miRNA-based therapeutic strategies show preclinical promise for KS management, particularly by restoring tumor-suppressive miRNAs or targeting oncomiRs. The development of nanoparticle delivery systems addresses critical limitations such as miRNA instability and ensures targeted delivery, representing a significant advance in therapeutic design. This review examines the multifaceted role of miRNAs in KS pathogenesis and explores innovative miRNA-based therapeutic interventions to combat this malignancy effectively.

Organelle contact sites are increasingly recognized as regulatory interfaces that coordinate lipid transfer, ion signaling, and metabolic adaptation. In neurons, communication among the endoplasmic reticulum (ER), lysosomes, and mitochondria is essential for cellular homeostasis. Recent studies have identified vacuolar protein sorting 13 homolog C (VPS13C), a lipid transport protein, as a key mediator of ER-lysosome tethering and as an important component of the response to lysosomal stress. Structural analyses show that VPS13 family proteins form elongated lipid transport channels that are proposed to facilitate phospholipid transfer between adjacent membranes. Following lysosomal damage, VPS13C is recruited to ER-lysosome contact interfaces, where it forms tethering bridges that may support membrane repair by enabling high-capacity lipid transfer from the ER to lysosomal membranes. Beyond membrane repair, these contact interfaces may also participate in broader organelle communication networks. ER-lysosome contacts can occur in proximity to ER-mitochondria junctions, potentially forming multi organelle signaling hubs that coordinate lipid redistribution, calcium signaling, and mitochondrial adaptation. These signals may influence downstream responses, including activation of TFEB and TFE3, which regulate lysosomal biogenesis and autophagy. Disruption of this contact site network has emerged as a potential contributor to Parkinson's disease. Loss of VPS13C function is associated with altered lysosomal homeostasis and intersects with pathogenic pathways involving α-synuclein aggregation, PINK1/Parkin-mediated mitophagy, and LRRK2 signaling. This review presents a framework in which ER-lysosome tethering is considered part of a staged cellular damage response linking membrane repair, metabolic coordination, and transcriptional adaptation.

The ubiquitous human gamma-herpesvirus Epstein-Barr virus (EBV) infects over 90% of adults globally and was the first human virus identified with oncogenic potential. EBV enters a lifelong persistence in the host via a finely regulated life-cycle comprising primary infection, latency and lytic reactivation. Within infected B-cells and epithelial cells, EBV encodes a distinct repertoire of microRNAs (miRNAs), primarily from the BART (BamHI A rightward transcript) and BHRF1 (BamHI H rightward open reading frame) clusters, which play pivotal roles in modulating both viral and host gene expression. These viral miRNAs contribute to key oncogenic processes: by dampening apoptotic responses (e.g., via targeting PUMA, Bim, and PTEN), promoting proliferation of latently-infected B-cells, inhibiting host immune responses (e.g., via down-regulation of CXCL-11 by miR-BHRF1-3), and promoting epithelial-mesenchymal transition (EMT) and metastasis through modulation of E-cadherin and other adhesion molecules. In human lymphomas, such as Burkitt lymphoma, Hodgkin lymphoma, and EBV-positive diffuse large B-cell lymphoma, the interplay of latent viral gene expression, miRNA-mediated regulatory networks, and host microenvironmental factors underlies malignant transformation and disease progression. Emerging evidence also supports the utility of EBV-encoded miRNAs as diagnostic and prognostic biomarkers in EBV-associated cancers. Importantly, therapeutic strategies aimed at interrupting viral miRNA function, restoring host tumor-suppressor pathways, and re-sensitizing tumor cells to immune surveillance hold promise. This review synthesizes current mechanistic insights into EBV-encoded miRNAs in oncogenesis, elaborates on their roles in lymphoma pathogenesis, and evaluates the translational potential of miRNA-targeted therapies in EBV-associated malignancies.

Fibroblasts are essential for tissue repair, but persistent activation of matrix-remodelling myofibroblasts can promote fibrosis, tissue stiffening and immune dysfunction. LRRC15 is a leucine-rich repeat-containing cell-surface protein enriched in selected activated mesenchymal compartments, with the strongest functional evidence arising from cancer-associated stroma. State-level evidence also links LRRC15 to a TGF-β-regulated extracellular matrix-remodelling myofibroblast state in idiopathic pulmonary fibrosis and to disease-specific myofibroblast programs in human skin, including inflamed hidradenitis suppurativa associated with scarring risk. However, LRRC15-specific causal evidence in physiological wound repair and pathological scarring remains limited. This review therefore considers LRRC15 positivity a context-dependent stromal state rather than a universal fibroblast lineage or intrinsically pathological identity. Focusing on pulmonary fibrosis and tumour stroma, with skin repair as a comparative framework, we integrate single-cell transcriptomics, spatial mapping, matrix biology and cancer immunology. Current evidence supports LRRC15 as a marker of activated stromal programs and, in selected tumour models, as a contributor to immunoregulatory stromal function, but does not establish universal control of fibroblast contractility, matrix persistence, or scar formation. We propose that temporal persistence and anatomical context may distinguish adaptive from maladaptive LRRC15-associated remodelling. Across tissues, these observations suggest related or convergent programs rather than a demonstrated conserved molecular identity. The proposed repair-to-pathology spectrum is therefore hypothesis-generating and requires validation through temporal lineage tracing, tissue-relevant LRRC15 perturbation, spatial protein analysis, and stage-specific therapeutic studies. LRRC15 is best viewed as a biological readout and potential targeting handle whose significance must be defined in each tissue context.

Diabetic steatohepatitis, now clinically framed within metabolic dysfunction-associated steatohepatitis (MASH), features progressive disruption of hepatic microarchitecture alongside sterile inflammatory microdomains. Farnesoid X receptor (FXR) activity is restrained by acetylation and p300 recruitment. CD38-driven NAD+ depletion also limits SIRT1 activity, suggesting a linked regulatory axis. We tested whether combined CD38 inhibition and FXR activation reprogram acetylation-dependent FXR complexes, restore hepatic tissue organization, and suppress NLRP3 inflammasome signaling. Male rats with diabetic steatohepatitis received vehicle, CD38 inhibition, FXR activation, or the combination. Outcomes included steatohepatitis activity score, fibrosis burden, lipid and glucose homeostasis, insulin resistance indices, and NLRP3 pathway activity, including caspase-1, IL-1β, and IL-18. Diabetic steatohepatitis induced hepatic architectural disorganization, dyslipidemia, insulin resistance, and activation of the NLRP3-caspase-1-IL-1β/IL-18 axis. Single-pathway modulation improved these abnormalities, whereas combined CD38 inhibition and FXR activation produced the greatest reductions in steatohepatitis activity score and the most consistent normalization of metabolic indices with no evidence of overt toxicity. Diabetic steatohepatitis tissue exhibited FXR hyperacetylation and increased FXR association with p300 and NLRP3; combination therapy reduced FXR acetylation and weakened both interactions. Pharmacologic disruption of SIRT1 or FXR partially reversed metabolic, inflammatory, and molecular effects, while selective inflammasome inhibition lowered inflammasome outputs without altering the CD38-NAD+-SIRT1 node. Together, coordinated restoration of NAD+/SIRT1 activity and FXR signaling reprograms FXR acetylation, disengages inflammasome signaling, and improves hepatic tissue organization in diabetic steatohepatitis.

Hepatic ischemia-reperfusion (I/R) injury is a major contributor to postoperative liver dysfunction and graft failure, driven by mitochondrial damage, innate immune activation, and downstream inflammatory amplification. Emerging evidence implicates the cGAS-STING pathway as a key upstream sensor of mitochondrial danger signals, while BET family proteins, particularly BRD4, function as epigenetic amplifiers that sustain inflammatory transcription. We hypothesized that simultaneous inhibition of STING signaling and BD1-selective BET bromodomains would provide enhanced protection against hepatic I/R injury by suppressing upstream pro-inflammasome signaling. Using a mouse model of hepatic I/R, we evaluated the effects of the STING inhibitor H-151 and the BD1-selective BET inhibitor GSK778, alone and in combination. Hepatic I/R induced marked mitochondrial oxidative stress, cytosolic mtDNA accumulation, activation of STING downstream signaling (TBK1, IRF3, NF-κB), increased BRD4 chromatin occupancy at inflammatory gene promoters, and robust inflammatory, inflammasome, and injury responses. Monotherapy with either H-151 or GSK778 partially attenuated these effects, whereas combined treatment produced broader suppression of mitochondrial stress, inflammatory transcription, inflammasome activation, neutrophil infiltration, and hepatocellular injury. Exploratory correlation analysis revealed coordinated associations linking mitochondrial stress, STING activation, BRD4-dependent transcription, inflammatory mediator production, inflammasome activity, and liver injury severity. Bliss independence and highest-single-agent analyses further indicated enhanced efficacy of the combined regimen across multiple mechanistic and injury endpoints. Collectively, these findings support a model in which STING signaling and BD1-dependent BET/BRD4 transcription cooperatively drive inflammatory amplification and inflammasome-associated hepatic I/R injury. Dual targeting of these pathways suppresses upstream pro-inflammasome signaling and mitigates ischemia-reperfusion-associated hepatic tissue remodeling.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by metabolic stress, inflammation, and fibrosis, with limited effective therapies. Thioredoxin-interacting protein (TXNIP) links hyperglycemia and oxidative stress to NLRP3 inflammasome activation, but the epigenetic mechanisms sustaining TXNIP induction in diabetic MASH remain unclear. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader that promotes inflammatory transcription through chromatin engagement. Here, we examined whether BRD4-associated regulation of TXNIP contributes to diabetic MASH and evaluated LT052, a BD1-biased BET bromodomain inhibitor with preferential BRD4 BD1 activity, in a streptozotocin-accelerated dietary rat model. Diabetic MASH caused severe steatohepatitis, fibrosis, insulin resistance, oxidative stress, NF-κB activation, TXNIP induction, and NLRP3 inflammasome activation. These changes were accompanied by increased BRD4 occupancy at the TXNIP promoter and elevated total hepatic histone H3 acetylation (Ac-H3K9). LT052 markedly improved liver histopathology, metabolic control, redox balance, and inflammatory outcomes, while reducing TXNIP expression, inflammasome activation, and downstream pyroptotic signaling. Mechanistically, LT052 reduced BRD4 occupancy at the TXNIP promoter and decreased total hepatic Ac-H3K9 without altering total BRD4 expression or nuclear BRD4 immunostaining, consistent with reduced BRD4-associated promoter engagement rather than altered BRD4 abundance or localization. Integrated analyses showed broad, dose-dependent improvement across MASH-relevant endpoints. These findings support further investigation of BD1-biased BET inhibition with LT052 as a therapeutic strategy for diabetic MASH.

The NLRP3 inflammasome responds to chemically and biologically diverse stimuli, yet growing evidence indicates that this apparent diversity converges on a limited set of structural and spatial licensing steps. Here, we argue that NLRP3 regulation is best understood through an assembly-centered framework rather than as another stimulus-centered catalog of activators. Cryo-electron microscopy (Cryo-EM), biochemical, and cell-biological studies support a model in which NLRP3 is maintained in inactive cage-like assemblies, undergoes nucleotide-dependent conformational rearrangements, engages NEK7, and nucleates ordered supramolecular complexes containing apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). We synthesize current evidence for structural licensing, interface-level restraint, subcellular trafficking, phase-separation-linked organization, and post-translational and proteostatic control of NLRP3 assembly. We then examine a less explored question with translational implications: whether peptide-scale regulators, particularly endogenous microproteins, may control defined assembly transitions. Available evidence supports the existence of synthetic peptides that inhibit inflammasome interfaces and of endogenous microproteins that intersect with inflammatory signaling. However, direct evidence that endogenous microproteins act as dedicated interface-mimic inhibitors of NLRP3 assembly remains lacking. This review integrates mature structural models of NLRP3 regulation with the emerging microprotein field while clearly distinguishing established mechanisms from plausible but unproven hypotheses. This perspective defines a mechanistically explicit agenda for future work, including rigorous validation of translated small open reading frames (smORFs), direct interaction mapping to defined NLRP3 surfaces, and quantitative testing of effects on assembly, signaling output, and cellular context.