Endometriosis is a common gynecological disease in which lipid metabolic dysregulation has been increasingly implicated. However, the specific metabolic changes in ectopic lesions and stromal cells remain poorly understood. It is also unclear whether these changes contribute to lipid droplet accumulation or how this process is controlled at the transcriptional level. Here, we report that ectopic stromal cells exhibit broad lipid remodeling, showing changes in phosphatidylcholines, lysophosphatidylcholines, sphingomyelins, and acylcarnitines. Both ectopic lesions and ectopic stromal cells showed increased triacylglycerol and total cholesterol levels, lipid droplet accumulation, and reduced E2F1 expression. Integrated epigenomic and transcriptomic analyses of patient-derived ectopic stromal cells, together with mechanistic validation, revealed that E2F1 transcriptionally activates MGLL, which encodes monoacylglycerol lipase, a lipolytic enzyme involved in lipid mobilization. Both in vitro and in vivo experiments showed that downregulation of E2F1 increased lipid droplet accumulation, whereas restoring MGLL expression partially reversed this effect. Consistently, targeted lipidomic analysis of ectopic stromal cells following MGLL knockdown showed increased levels of several diacylglycerol species and alterations in sphingomyelin profiles. In summary, our findings suggest that E2F1 downregulation reduces MGLL expression and impairs lipid mobilization, which may contribute to lipid droplet accumulation and endometriotic lesion growth.

Cardiac aging increases susceptibility to cardiovascular diseases. Cellular senescence may be involved in the development of age-related cardiac diseases. Extensive evidence derived from both clinical and experimental studies suggest that the Type 2 Angiotensin II receptor (AT2R) exerts a potent cardioprotective effect, however, its potential contribution to age-related cardiac complications remains unknown. In this study we used AT2R knockout (AT2-KO) and wild-type mice (WT) both aged (18-21-month-old) and young (4-5-month-old) and evaluated the repercussions cardiac of aging. Old AT2-KO mice exhibited impaired systolic and diastolic cardiac function and exacerbated fibrosis accompanied by increased fibrotic markers expression. The absence of AT2R accelerated the cardiac senescence process in old mice, evidenced by early increase in p53 and p21. In addition, aged AT2-KO mice showed increased expression of Senescence-Associated Secretory Phenotype (SASP) components, activation of cardiac NF-kB and NLRP3-inflammasome followed by increased levels of cardiac IL-1β and IL-18 compared to aged WT mice. AT2R deficiency also resulted in significant DNA damage even in young animals and it was associated with a 5-month reduction in median lifespan (26 months for AT2R-KO vs. 31 months for WT). These findings suggest potential mechanisms whereby AT2R acts as a key mediator of cardiac senescence and cardioprotection during aging.

SARS-CoV-2 coronavirus infections are associated with long term vascular dysfunction, yet the drivers remain unclear. We hypothesized that remnant Betacoronavirus antigens remain in circulation and organs, act as danger-associated molecular patterns (DAMPs), and sustain inflammation. We used human patient samples, mouse virus infection models and in vitro techniques to define the role of remnant virus proteins after coronavirus infection. In patients, both coronavirus derived S- and N-proteins persisted months after infection even with S and N specific antibodies present in circulation. A high-N-protein subgroup exhibited increased vWF and vWF/ADAMTS13 ratio and elevated IL-6/IFN-γ plasma levels indicative for endothelial activation and low grade inflammation. Extracellular vesicles bearing VCAM-1/PDGFR were increased 4-6 months after infection. In animal models, virus infection was resolved within ten days after pulmonary infection in the lung. Remnant virus proteins accumulated in organs after full virus resolution and were linked to localized inflammation and endothelial cell activation 17 days post infection. Virus tropism was not required for virus protein presence in organs. Prednisolone treatment after viral clearance reduced remnant protein-associated vascular inflammation. In vitro, N- and S-protein directly induced a proinflammatory NF-κB response in liver spheroids and endothelial cells, with N-protein signalling being TLR4-dependent. Together, these data identify remnant coronavirus proteins as active inflammatory DAMPs that promote post-infectious endothelial activation and might define an antigen-linked vascular inflammatory phenotype after SARS-CoV-2 infection.

Liver fibrosis is a dynamic and potentially reversible consequence of chronic liver injury, shaped by persistent inflammation, metabolic disturbance, and impaired tissue repair. Accumulating evidence indicates that, rather than operating as independent processes, immune activation, metabolic reprogramming, and cellular senescence are closely interconnected during fibrogenesis, jointly driving hepatic stellate cell (HSC) activation, ductular reaction, and excessive extracellular matrix deposition. In this review, we synthesize current understanding of how innate and adaptive immune responses, metabolic remodeling in hepatocytes and HSCs, and senescent cells with their senescence-associated secretory phenotype cooperatively sustain fibrotic progression, with particular emphasis on bidirectional and context-dependent cross-talk. We further highlight key regulatory nodes-including NF-κB, AMPK-mTOR, SIRT1/3, the NLRP3 inflammasome, and the YAP/TAZ pathway-that integrate signals across these interconnected pathways. Recent advances in multi-omics profiling, spatial transcriptomics, and organoid-based models have provided new opportunities to interrogate this integrated network at cellular and spatial resolution. From a translational perspective, therapeutic strategies targeting immunometabolic regulation, inflammasome activation, and cellular senescence, especially when combined with cell-type-specific intervention approaches, may offer promising avenues for restoring tissue homeostasis and reversing liver fibrosis.

Brain ischemia is a leading cause of morbidity and mortality in the aging population, yet no effective neuroprotective interventions currently exist. This therapeutic gap stems from two key challenges: the inability to deliver neuroprotective drugs before reperfusion and limited understanding of post-reperfusion events leading to delayed neurodegeneration. Zn2+ is an important contributor to ischemic brain injury, with mitochondrial Zn2+ uptake playing a central role in its neurotoxic effects. Ongoing Zn2+ accumulation occurs through the mitochondrial Ca2+ uniporter (MCU) in selectively vulnerable CA1 neurons after transient ischemia, contributing to delayed mitochondrial dysfunction. We previously demonstrated that post-ischemic administration of the non-selective MCU antagonist, ruthenium red attenuated neuronal damage in both an ex vivo oxygen glucose deprivation (OGD) mouse brain slice model and in an in vivo rat cardiac arrest (CA) model. In the present study, we test post-ischemic treatment with Ru265, a novel selective MCU blocker, in both ischemic models. In the slice model, OGD induced delayed Zn2+ accumulation in CA1 neuronal mitochondria (as previously reported), followed by late-onset persistent mitochondrial depolarization and sustained elevation of cytoplasmic Ca2+ levels, indicating loss of Ca2+ homeostasis. Application of Ru265 after OGD termination inhibited the mitochondrial Zn2+ accumulation and largely prevented subsequent mitochondrial depolarization and loss of cytosolic Ca2+ homeostasis. In the CA model, intravenous Ru265 administration during cardiopulmonary resuscitation largely mitigated mitochondrial damage, markedly reduced neuronal injury and improved behavioral outcomes 20-24 hours after ischemia. These findings suggest that post-ischemic MCU blockade may constitute a promising neuroprotective therapeutic strategy.

The central medial thalamic nucleus (CM), a key component of the thalamic intralaminar nuclei, receives nociceptive inputs from the lateral parabrachial nucleus and is implicated in pain processing. However, the specific neuronal subtypes and downstream pathways that mediate these functions remain poorly defined. Here, we combined tract tracing, immunofluorescence, in situ hybridization, chemogenetics, fiber photometry, and behavioral tests to investigate the role of calretinin-positive (CR+) neurons in the CM (CMCR+) and their projections to the anterior insular cortex (aIC) in nociceptive transmission. Our results demonstrated that activation of the CM promotes both pain and anxiety-like behaviors. The CM harbors a substantial population of excitatory CR+ neurons that are activated by nociceptive stimulati, as indicated by Fos expression and elevated calcium signals. Chemogenetic activation of CMCR+ neurons in control mice induced mechanical, cold, and thermal hypersensitivity, along with anxiety-like behaviors. Conversely, chemogenetic inhibition of these neurons in a CFA-induced model of chronic inflammatory pain markly alleviated pain hypersensitivity and comorbid anxiety. Anatomical tracing revealed that CMCR+ neurons send dense projections to the aIC. Functional manipulation of the CMCR+-aIC pathway confirmed its critical role in nociceptive transmission and pain-related affect behaviors. Together, our results identify a thalamocortical circuit that mediates nociceptive signaling and affective comorbidity in chronic pain, highlighting CMCR+ neurons as a potential therapeutic target for treating refractory pain and its emotional components.

Genome-wide association studies have identified numerous susceptibility loci for spontaneous coronary artery dissection (SCAD), yet translating non-coding genetic associations into molecular mechanisms remains a major challenge. In the present issue, Liu et al. provide functional evidence linking the SCAD-associated variant rs13128814 at the ZNF827 locus to the regulation of a vascular smooth muscle cell (SMC)-specific enhancer. The authors show that the risk allele creates a de novo binding site for nuclear factor I (NFI) transcription factors within a developmentally regulated putative enhancer, implicating ZNF827 as a previously unrecognized regulator of vascular biology. The present work illustrates both the power and the complexity of moving from statistical genetic associations to mechanistic insight. It highlights a regulatory relationship between NFI transcription factors and ZNF827 during SMC differentiation, providing new insights into the molecular basis of SCAD. Importantly, the study also underscores the context-dependent nature of enhancer activity and emphasizes the need for a deeper understanding of enhancer grammar, chromatin context, and transcription factor cooperativity to accurately predict the functional consequences of non-coding variation. Overall, the work advances our understanding of SCAD pathogenesis while illustrating the broader challenges of decoding regulatory variation. Integrating human genetics with functional genomics, genome engineering, and predictive computational models will be essential for establishing causal links between non-coding variation and vascular disease.

Subclinical hypertensive heart disease (SHHD) is a precursor to heart failure and ultimately progresses to impaired left ventricular systolic function, which is characterized by myocardial hypertrophy leading to compromised contractility and by myofibroblast proliferation and activation leading to decreased myocardial compliance. However, the epigenetic mechanisms that coordinate fibroblast-mediated fibrosis during pressure overload remain incompletely understood. Here, we identified the histone demethylase Kdm2a as an important regulator of cardiac remodeling in a mouse transverse aortic constriction (TAC) model. Kdm2a was up-regulated and enriched in activated cardiac fibroblasts during TAC-induced remodeling. Fibroblast-enriched Kdm2a knockdown improved cardiac function, reduced myocardial hypertrophy, and markedly attenuated interstitial and perivascular fibrosis in TAC hearts. In cultured primary cardiac fibroblasts, profibrotic stimulation increased Kdm2a expression, whereas CRISPR-mediated Kdm2a knockout suppressed fibroblast activation, collagen production, and extracellular matrix (ECM) deposition. Conversely, Kdm2a overexpression enhanced profibrotic responses. RNA sequencing and network analyses further showed that Kdm2a modulates ECM-associated pathways and remodeling-related gene programs. Mechanistically, Kdm2a modulation was associated with both global and locus-specific remodeling of H3K36me2. Kdm2a up-regulation was accompanied by altered bulk H3K36me2 levels, while CUT&RUN-qPCR demonstrated locus-specific changes in H3K36me2 enrichment at remodeling-associated genes, including Col1a1, Col4a1, and Cdkn2b/p15. These findings suggest that Kdm2a reshapes the H3K36me2 chromatin landscape in a context- and locus-dependent manner to promote fibroblast activation and ECM remodeling and identify Kdm2a as an epigenetic driver of fibroblast-mediated cardiac remodeling and a potential therapeutic target for sustained pressure overload-induced heart failure.

Hepatotoxicity assessment is paramount in drug development and food safety. Traditional in vitro models suffer from insufficient physiological relevance and poor functional reproducibility. Liver organoids have rapidly emerged as three-dimensional culture models capable of recapitulating multicellular interactions and key hepatic functions, offering unprecedented tools for toxicity assessment. They exhibit broad potential in modeling diverse toxicity phenotypes, including acute liver injury, chronic cumulative toxicity, cholestasis, and fibrosis. Currently, organoids are extensively utilized in drug hepatotoxicity evaluation, environmental contaminant screening, drug-drug interaction profiling, and the determination of personalized safety margins. Despite ongoing challenges in functional maturation and standardized derivation, the integration of multidisciplinary technologies and refined ethical frameworks positions liver organoids as a central platform for future toxicity testing. They will propel the advancement of precision toxicology and precision medicine, serving as a pivotal tool for hepatobiliary disease research. The present review systematically chronicles the developmental trajectory of liver organoids, their versatile applications in toxicity assessment, and recent technological breakthroughs. Furthermore, we explore their translational potential in hepatobiliary surgery, personalized nutritional interventions, and preclinical research, aiming to provide a comprehensive reference for researchers and clinicians in related fields.

To explore the role of gut microbiota and bile acid metabolism in Acute myeloid leukemia (AML), we analyzed samples from 29 patients via 16S rDNA sequencing and LC-QTOF-MS, and performed functional studies on Enterococcus faecalis and hyodeoxycholic acid (HDCA). Results revealed a dynamic shift in gut microbiota diversity during treatment, which recovered after therapy. Notably, the abundance of Enterococcus at baseline was significantly correlated with clinical response after treatment. Furthermore, fecal microbiota transplantation (FMT) using E. faecalis reduced in vivo leukemia burden and increased levels of bile acids such as HDCA. In vitro analyses demonstrated that HDCA suppresses AML cell growth and promotes apoptosis through inhibition of NF-κB, mitochondrial dysfunction, and cell cycle arrest. These findings were corroborated in a mouse model, where HDCA delayed leukemia progression and improved survival. Clinically, higher baseline serum HDCA correlated with greater gut microbiota α diversity and was associated with complete remission. In summary, Enterococcus levels and baseline HDCA are linked to AML treatment outcomes. E. faecalis FMT ameliorates AML with concurrent rises in fecal HDCA, while HDCA exerts anti-leukemic effects by targeting NF-κB, disrupting mitochondrial integrity, arresting the cell cycle, and triggering apoptosis.

Although circular RNAs (circRNAs) have been implicated in acute kidney injury (AKI), their functional mechanisms beyond acting as miRNA sponges remain poorly understood, and the role of N6-methyladenosine (m6A) modification in circRNA-mediated regulation in AKI is yet to be explored. Here, we identify a novel mechanism by which the m6A-modified circRNA circNfix contributes to the regulation of septic AKI (SAKI). In tubular epithelial cells (TECs), down-regulation of RBM47 reduces circNfix expression during SAKI. m6A-modified circNfix scaffolds the E3 ligase HECTD1 to induce K48-linked polyubiquitination and proteasomal degradation of the m6A reader YTHDF2. This stabilizes DAPK2 mRNA, a key target of YTHDF2, inhibiting NF-κB activation, thereby reducing TEC apoptosis and inflammation. In mouse models of SAKI and ischemia-reperfusion injury-AKI, AAV-mediated circNfix delivery lowered YTHDF2, suppressed inflammation, improved renal function, and attenuated damage. In SAKI patients, circNfix levels in plasma and urine were significantly decreased, negatively correlated with serum creatinine. Urinary and plasma circNfix showed diagnostic potential. Our study reveals a mechanism where an m6A-modified circRNA contributes to AKI progression by degrading its reader protein, suggesting that circNfix may represent a potential therapeutic target and non-invasive biomarker.

Interferon-λ receptor (IFNLR), a heterodimer composed of IFNLR1 and IL‑10Rβ, mediates IFN‑λ‑driven fibrotic effects. This study investigated the involvement of IFNLR1+ monocytes/macrophages in orchestrating pro-fibrotic immune microenvironment. Flow cytometric analysis of peripheral blood showed that IFNLR1[+] monocytes were elevated in patients with chronic hepatitis B virus (HBV) infection (CHI) and patients with HBV‑related liver cirrhosis (LC), compared with healthy control (HC). These cells also displayed a CCR2ʰ[1]CCR5ʰ[1]CX3CR1ʰ[1]CD86ʰ[1]HLA-DRʰ[1]CD163ʰ[1]MERTKʰ[1] phenotype with an IL‑10ʰ[1]TNF‑αʰ[1] cytokine profile. Hepatic fibrosis was induced in wild‑type and Ifnlr1‑knockout (Ifnlr1-/-) mice using carbon tetrachloride and recombinant adeno‑associated virus 8‑1.3HBV. Ifnlr1 deficiency downregulated CCR2 and CCR5 expression on monocytes/macrophages, attenuated collagen deposition, but enhanced HBV-DNA replication. In vitro, bone marrow derived macrophages (BMDMs) were co-cultured with hepatic stellate cells (HSCs) or naive CD4+ T cells to assess the functional impact of IFNLR1+ macrophages. Concurrently, the involvement of lipid metabolism in IFN‑λ/IFNLR1‑mediated macrophage regulation was examined using liver X receptor (LXR) agonists/antagonists. Ifnlr1-/- BMDMs exhibited a diminished capacity to activate HSCs and drive regulatory T cells differentiation. Mechanistically, IFN-λ-IFNLR1 signaling suppressed LXR-dependent lipid metabolism, thereby promoting tumor necrosis factor (TNF)-α and IL-1β production, and LXR pathway inhibition favored M1-macrophage polarization. Collectively, IFNLR1 identifies a pro-fibrotic and immunoregulatory monocyte/macrophage subset. Targeting IFNLR1-LXR axis may represent promising anti-fibrotic strategies for HBV-related liver fibrosis.

Aging has been associated with hypertension, end-organ damage, and cognitive dysfunction. The protective axis of the renin-angiotensin system, consisting of angiotensin converting enzyme 2 (ACE2)/angiotensin (Ang)-(1-7)/Mas receptor (MasR), exerts anti-hypertensive and cerebroprotective effects. Thus, we aimed to evaluate whether aging and hypertension may be associated with region-specific changes in the ACE2/Ang-(1-7)/MasR axis in the brainstem (BS), hypothalamus (Hypot), hippocampus (Hippo), and cerebral cortex (CC) of Wistar rats and spontaneously hypertensive rats (SHRs) at different ages. Ang-(1-7) levels were measured by radioimmunoassay, and ACE2 and MasR expression by immunoblotting. In Wistar rats, Ang-(1-7) levels decreased with age in all brain areas. At a prehypertensive stage (1 month of age), SHRs exhibited lower Ang-(1-7) levels than Wistar rats in BS, Hypot, Hippo, and CC. Contrary to Wistar rats, Ang-(1-7) levels increased at 3 months and subsequently decreased at 12 months in SHRs. No differences in Ang-(1-7) levels between both strains were found at 3 and 12 months of age. In line with the reduced hypothalamic Ang-(1-7) levels, MasR and ACE2 protein abundance were also decreased in the Hypot of 1-month-old SHRs compared to age-matched Wistar rats. In contrast, MasR expression was higher in BS of 1-month-old SHRs compared to age-matched Wistar rats, suggesting a compensatory response. At 1 month of age, ACE2 and MasR protein levels did not differ between strains in the Hippo or CC. We conclude that abnormal changes in the expression of the brain ACE2/Ang-(1-7)/MasR axis early in life may predispose to the development of hypertension with age.

In health, the autonomic nervous system modifies secretion of the islet hormones insulin, glucagon, and pancreatic polypeptide (PP). Uniquely, PP secretion is nearly fully dependent upon parasympathetic innervation. In people with cystic fibrosis (CF), physiological secretion of all three hormones is impaired, but the role of the autonomic nervous system in this dysfunction is unknown. We thus examined PP secretion and pancreatic neuronal immunostaining in humans and ferrets with CF. Both young humans and ferrets with CF had greatly impaired PP secretion, despite an abundance of islet PP cells and intact PP secretion from perifused CF ferret islets. Pan-neuronal staining in the pancreas was nearly absent from CF humans and of aberrant morphology and distribution in CF ferrets. Parasympathetic neuronal staining was nearly absent in both ferret and human CF pancreata. When exocrine pancreatic disease was delayed until after the first month of life by administering a CFTR modulator in CFTRG551D homozygous ferrets, there was preservation of pancreatic neuronal markers and restoration of PP secretory responsiveness to oral glucose. We conclude that the CF pancreas is impacted by a loss and remodeling of its innervation, secondary to early-life pancreatic disease, likely contributing to impaired islet hormone secretion.