The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent endothelial-to-mesenchymal transition (Endo-MT). In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 partially recovered the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint HAND2 as an essential regulator of the endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.

Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring Tuberous Sclerosis Complex 1 (TSC1) mutations exhibits more aggressive behavior. TFEB is a master regulator of lysosomal biogenesis and cell fate. We analyzed human normal and HCC tissue arrays for TFEB and CK19 expression, as well as bulk and single-cell RNA-seq datasets from mouse and human HCC, to define TFEB-associated transcriptional programs. We performed biochemical, histological, metabolomic, and transcriptomic analyses in liver-specific Tsc1 knockout (L-Tsc1 KO) and L-Tsc1,Tfeb double KO (DKO) mice. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-Tsc1 KO mice showed increased hepatocyte plasticity, decreased HFN4α, increased YAP1 activation, and spontaneous HCC with increased SOX9 and CK19-positive biliary epithelial cell (BEC)-like cells at 8-12 months. Deletion of Tfeb dampened hepatic metabolic reprogramming and hepatocyte fate changes and inhibited tumor progression in L-Tsc1 KO mice. Increased TFEB activity was associated with increased YAP and SOX9 gene expression and high-grade malignant HCC in humans. These findings indicate that loss of hepatic TSC1 leads to non-canonical TFEB activation, promoting hepatocyte plasticity and tumor heterogeneity associated with high-grade malignancy in both mouse and human HCC.  .

Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovers conserved genetic and environmental factors underlying PMOS, identifies susceptible cell types and organs, and elucidates mechanisms linking PMOS to subsequent pathologies. For instance, we show that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary-heart signaling circuits modulate cardiac function with aging. We further identify ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin and glucose levels, as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.

The success of allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (aGVHD). We have previously reported that neutrophils can exacerbate tissue damage caused by conditioning regimens. Pegtarazimod is a synthetic peptide, derived from the capsid protein of human astrovirus serotype 1, that was shown to reduce neutrophil effector functions. Therefore, we evaluated the therapeutic activity of pegtarazimod against aGVHD. Pegtarazimod significantly reduced aGVHD-related mortality, histological aGVHD severity, and pro-inflammatory cytokines in multiple in vivo mouse models, while maintaining the anti-leukemia effect. Mechanistically, pegtarazimod reduced inflammation by decreasing ROS production as investigated using allo-HCT recipient mice with genetic inactivation of NADPH oxidase (NOX2) in the bone marrow. In addition to the anti-inflammatory effect, pegtarazimod protected intestinal organoids against TNF-induced toxicity and oxidative DNA damage. In the phase-2 clinical trial AURORA, pegtarazimod treatment was well-tolerated in patients with corticosteroid-refractory (SR) aGVHD (NCT06343792) with an overall response rate (ORR) of 4/7 patients at day 28. In summary, pegtarazimod reduced aGVHD in mice by suppressing pro inflammatory neutrophil effector functions and preserving enterocyte integrity. The clinical trial data support tolerability of pegtarazimod in aGVHD patients and further studies are needed to determine efficacy.

Dietary cholesterol and de novo cholesterol synthesis in the liver use reciprocal coordination to maintain cholesterol homeostasis. However, high level of dietary cholesterol still promotes excessive cholesterol accumulation in the liver, leading to metabolic dysfunction-associated steatohepatitis (MASH), yet the mechanisms remain poorly understood. Here we show that hepatic S100A11, a member of the S100 family of calcium-binding proteins, positively responds to the dietary cholesterol level and is involved in hepatic cholesterol metabolism. S100A11 localizes to the endoplasmic reticulum and can bind to cholesterol. In vivo and in vitro, hepatic overexpression of S100A11 led to SREBP2 activation to promote cholesterol synthesis, uptake, and accumulation, consequently exacerbating steatohepatitis. In contrast, inactivation of S100A11 had opposite effects and improved steatohepatitis. Mechanistically, S100A11 triggers the non-canonical entry of SREBP2 into the nucleus through a S100A11-ANXA1-KPNB axis, distinct from the well-known INSIG-SCAP pathway or Caspase2 pathways. Therefore, our work identifies S100A11 as a regulator of liver cholesterol metabolism, providing a promising target to treat MASH and hypercholesterolemia.

Effective psychotherapeutic interventions for post-traumatic stress disorder (PTSD) rely on fear extinction to suppress maladaptive fear responses, yet their long-term efficacy is limited by high relapse rates. Notably, extinction involves not only fear inhibition but also affective engagement. However, whether and how internal affective components contribute to extinction retrieval and long-term persistence remain unclear. Here, we demonstrate that positive affective experiences arising during extinction govern the long-term persistence of extinction and resistance to spontaneous recovery. We identify a subpopulation of medial prefrontal cortex (mPFC) extinction neurons projecting to supramammillary nucleus glutamatergic (SuMGlu) neurons that encodes positive affective experience during extinction and selectively governs long-term extinction persistence. This ensemble is spatially, anatomically, and transcriptionally distinct from mPFC extinction neurons projecting to zona incerta somatostatin-expressing (ZISST) neurons, which primarily support extinction retrieval. Transcriptomic profiling reveals enrichment of sirtuin 1 (Sirt1) within SuM-projecting extinction ensembles, and bidirectional manipulation of SIRT1 alters extinction relapse vulnerability in a PTSD mouse model. These findings provide a cortical-hypothalamic framework incorporating molecular features that governs the long-term persistence of fear extinction and resistance to relapse through positive affective processes.

Loss-of-function mutations in PSMB8/beta5i and other components of the 20S proteasome result in multi-organ diseases, such as Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. Neurocognitive dysfunction associated with CANDLE suggests that proteasomal mutations may impact neuronal function and development early in life. We generated cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) made from CANDLE patients. The COs from CANDLE iPSCs exhibited impaired neuronal development when compared to COs from healthy control iPSCs. Impaired neuronal maturation in CANDLE COs was correlated with increased polyamines, which were also elevated in CANDLE patient CSF. The proteasome-regulated Ornithine decarboxylase (ODC), the rate limiting enzyme in polyamine biosynthesis, was elevated in CANDLE neurons. Inhibition of ODC reversed polyamine overproduction and repaired neuronal maturation in CANDLE COs, suggesting a potential therapeutic avenue for intervention. These findings demonstrate that dysfunction of the proteasome affects neuronal development through overproduction of polyamines via dysregulation of ODC and offer insight into potential therapeutic strategies for CNS-related proteasomal dysfunction.

Background Autoimmune diseases (ADs) often co-occur within individuals and families, indicating shared genetic risk factors. However, the composition of genetic overlap across autoimmunity is largely unknown. Methods This nationwide study included 6,336,615 individuals born in Sweden between 1932 and 1983, comprising 3,839,400 full-sibling pairs. Based on national heath-registers, 22 ADs were identified from 1969-2013. Aggregation and co-aggregation of ADs among siblings was used to estimate pairwise genetic correlations of ADs under a liability-threshold model. Network analysis and principal component analysis was used to characterize the structure of shared genetic risk across ADs. Results A total of 707,995 individuals (11.2%) were diagnosed with at least one AD. The studied ADs formed a network of significant genetic correlations (mean rg = 0.24, range 0.08-0.84) with clusters of more closely related ADs (rg ≥ 0.3). We found no evidence of a significant universal factor predisposing to autoimmunity. Conclusions This study demonstrates that ADs share substantial cluster-specific genetic overlap that largely aligns with affected tissue types, leading to distinct groupings of connective tissue diseases, gastrointestinal disorders, and endocrinopathies, whereas diseases of the nervous system show limited genetic cohesion. This suggests that shared biological mechanisms may drive coaggregation within disease groups. Clinically, these insights highlight the importance of monitoring patients and their relatives for related autoimmune disorders. Funding The Swedish Society of Medicine, Region Värmland's County Research Council, The Swedish Research Council, the Knut and Alice Wallenberg Foundation, The Regional Agreement on medical training and Clinical research (ALF) between Stockholm County Council and Karolinska Institutet.

We reported LINGO1 as a potential marker on Ewing sarcoma cells that could enable targeted drug delivery, improving treatment effectiveness while reducing side effects.

The cGAS/STING pathway is a central innate immune DNA-sensing system that links aberrant DNA species to innate immune and stress-response transcriptional programs and has emerged as a key regulator of tumor-immune interactions. In cancer, pathway outputs are shaped by interconnected downstream signaling modules, including type I IFN, NF-κB, autophagy, and stress-metabolic checkpoints, as well as by stringent spatial and biochemical regulation of both cGAS and STING. When activation is acute and appropriately compartmentalized, cGAS/STING signaling promotes antitumor immunity across multiple cellular compartments in the tumor microenvironment, supporting DC cross-priming and cytotoxic lymphocyte responses. In contrast, chronic or dysregulated activation rewires downstream signaling toward stress-adaptive and inflammatory programs that promote tumor progression, metastasis, and immune dysfunction, including deleterious effects in lymphocytes and the induction of suppressive myeloid and B cell populations. Here, we examine how context determines the consequences of cGAS/STING activation in cancer, review emerging therapeutic strategies that modulate this pathway, and discuss how its antitumor potential can be maximized while minimizing systemic toxicity and immune dysregulation.