Molecular Metabolism

Semaglutide has shown benefit in metabolic dysfunction-associated steatohepatitis (MASH), but real-world evidence across longitudinal liver phenotypes remains limited, particularly regarding how liver remodeling relates to weight loss and dose exposure. Using a de-identified federated electronic health record network spanning more than 29 million patients in the United States, including 489,785 semaglutide-treated adults, we analyzed 6,734 patients with baseline liver disease burden. We find that higher attained pre-landmark (0-2 years) semaglutide dose was associated with lower post-landmark (2-4 years) risk of steatohepatitis, alcoholic liver disease, and all-cause mortality, whereas greater pre-landmark weight loss was associated with lower post-landmark risk of steatohepatitis, steatotic liver disease, and hepatorenal syndrome, indicating distinct dose- and weight-linked patterns of long-term liver benefits. These associations were notable because semaglutide prescribing was generally lower during the post-landmark period, raising the possibility of durable benefit beyond peak exposure. Towards better understanding mechanistic bases for liver protection, we performed a complementary longitudinal study of 326 adults with paired noninvasive liver elastography measurements before and after treatment initiation. Median liver stiffness decreased from 4.85 [3.02 - 7.20] to 3.9 [2.6 - 5.8] kPa after semaglutide initiation (median change = -0.38 kPa; p<0.001), with 194 of 326 patients (59.5%) showing lower follow-up stiffness. A clinically meaningful reduction of at least 20% was observed in 133 of 326 patients (40.8%), and 69 of 326 (21.2%) shifted to a lower fibrosis stage by prespecified elastography thresholds. Larger improvements were also seen in patients with higher baseline stiffness (p<0.001); notably 80% of patients with cirrhosis-range baseline stiffness ([&ge;]12.5 kPa) achieved [&ge;]20% improvement versus 29.5% with minimal baseline disease (p <0.001). The proportion achieving at least 20% stiffness improvement was similar across weight-loss strata, including patients with no weight loss or weight gain and those with at least 10% weight loss (38.0% in each group), and liver stiffness change showed negligible correlation with changes in weight, BMI, HBA1c, alanine aminotransferase, or aspartate aminotransferase. To provide biological context, single cell RNA analyses demonstrated sparse overall hepatic GLP1R expression (0.0239%), with enrichment in non-parenchymal niches including cholangiocytes, intrahepatic cholangiocytes, liver sinusoidal endothelial cells, and hepatic stellate cells implicated in fibrogenesis and vascular remodeling. Together, this real-world evidence suggests diverse liver benefits for semaglutide beyond weight-loss with intricate dose response relationships.

GLP-1 receptor agonists induce substantial weight loss, but the extent to which lean tissue and physical function are preserved in routine care remains poorly understood. Using an EHR-linked body-composition digital phenotyping pipeline with LLM-based extraction, we performed a large-scale longitudinal analysis of 670,422 first-episode GLP-1RA users, including 456,742 treated with semaglutide and 213,680 treated with tirzepatide. Among these, 7,965 individuals with paired pre- and post-initiation body-composition measurements were analyzed over 12 months. Tirzepatide was associated with greater relative lean body mass (LBM) loss than semaglutide at each measured time point, with excess LBM losses of 1.1%, 1.5%, 1.3% and 2% at 3, 6, 9 and 12 months, respectively. A Depletive GLP-1 metabotype, defined as >20% total body weight (TBW) loss with >5% LBM loss, was significantly more frequent with tirzepatide than semaglutide during the first year of therapy (10.3% versus 6.7%, p<0.001). By contrast, a Prime GLP-1 metabotype, defined as >10% TBW loss with <5% LBM loss, was numerically more frequent with semaglutide than tirzepatide, but not significantly so (12.3% versus 11.8%, p=0.66). Higher drug dose and longer exposure were associated with progressively greater LBM decline in both treatment groups (both p<0.001). Among 3,746 examined EHR phenotypes, baseline musculoskeletal pain emerged as the most significant correlate of greater LBM loss (BH-adjusted q<0.001): cervicalgia (semaglutide, -4.1 percentage points; tirzepatide, -14.3 percentage points) and knee pain (semaglutide, -4.8 percentage points; tirzepatide, -13.4 percentage points), consistent with mobility-limited patients being more vulnerable to lean-tissue depletion during incretin therapy. Analysis of EHR notes for on-treatment functional features showed reduced exercise tolerance was the strongest correlate of greater LBM loss, increasing by 7.2 and 11.1 percentage points in semaglutide- and tirzepatide-treated patients, respectively. An independent analysis of all available Single-cell RNA-seq data from human musculature showed broader GIPR+ cellular distribution than GLP1R+ cells across immune, stromal, vascular, and contractile compartments, providing plausible biological context for the greater LBM loss observed in routine care with tirzepatide (dual GLP1R-GIPR agonist) relative to semaglutide (GLP1R-specific agonist). In this observational study, greater weight-loss efficacy did not necessarily translate into more favorable body-composition outcomes, underscoring the need for clinical decision-making and trial designs that maximize each patient's likelihood of achieving a Prime GLP-1 metabotype.

Background & AimsMetabolic disorders such as dyslipidemia, metabolic dysfunction-associated steatotic liver disease (MASLD), and diabetes are promoted by chronic pro-inflammatory and pro-oxidative states. Paraoxonase 1 (PON1), a liver-derived HDL-associated enzyme, plays an important antioxidant role by hydrolyzing oxidized lipids and protecting against oxidative stress- induced damage. Genetic variation in PON1, particularly in promoter and coding regions, modulates enzyme expression and activity, thereby influencing susceptibility to metabolic and cardiovascular diseases. This study investigated the genetic determinants of serum paraoxonase (PONase) activity and their relationship with dysmetabolic phenotypes. MethodsA genome-wide association study was conducted in 922 Portuguese individuals from the PREVADIAB2 cohort. Genetic variants and haplotypes related to PONase activity were analyzed, and associations with dysglycemia and liver fibrosis were evaluated in individuals aged over 55 years. ResultsWe identified two key PON1 variants as determinants of PONase activity: rs2057681 (in strong linkage disequilibrium with the non-synonymous Q192R variant) and rs854572 (located in the promoter region). Analysis of rs854572-rs2057681 haplotypes revealed that specific combinations differentially modulate PONase activity and confer risk or protection for dysglycemia and liver fibrosis, depending on the rs2057681 genotype context. Notably, although PONase activity was strongly associated with PON1 variants, it did not directly correlate with dysmetabolic phenotypes, suggesting that genetic context and haplotype structure, rather than enzyme activity alone, shape disease susceptibility. ConclusionsThese findings highlight the complex genetic architecture of PON1 and its role in metabolic disease risk, supporting the use of PON1 genetic information to uncover predisposition to dysmetabolic conditions. Our results provide insights into the interplay between PON1 genetics, enzyme function, and dysmetabolism, with implications for risk stratification in metabolic liver disease. Lay SummaryPON1 is a liver-derived gene that encodes an enzyme involved in protection against oxidative stress, a key contributor to metabolic liver disease and diabetes. In this study, we found that specific combinations of PON1 genetic variants are associated with abnormalities in blood glucose regulation and with markers of liver fibrosis. These associations were dependent on genetic configuration rather than enzyme activity alone, suggesting that PON1 genetic information may help identify individuals at higher risk of metabolic liver disease.

Intermuscular adipose tissue (IMAT) expansion is closely associated with cardiometabolic disease, yet its cellular organization and regulatory mechanisms remain poorly defined. Here, we define a human IMAT gene signature using bulk transcriptomics and identify candidate regulators for IMAT function including adipogenic transcription factor early B-cell factor 2 (EBF2). To determine how these programs are organized in situ, we mapped this signature in a mouse model of diet-induced CMD using spatial transcriptomics. We found that IMAT expansion occurs within discrete stromal niches surrounding muscle fibers, characterized by coordinated activation of adipogenic, extracellular matrix, inflammatory, and metabolic pathways. Spatial analyses showed that fibro-adipogenic progenitor (FAP) abundance does not predict adipocyte formation, supporting a model of localized and context-dependent lineage transitions. Cross-species comparison revealed partial conservation of human IMAT gene programs, validating the mouse model and highlighting species-specific features. Functional experiments in human primary myoblasts showed that EBF2 is sufficient to induce adipogenic reprogramming. Our findings establish IMAT as an active, spatially organized remodeling niche and identify lineage plasticity as a central mechanism driving its expansion in metabolic disease

Background: The glucagon-like peptide-1 receptor (GLP1R) is a key regulator of glucose metabolism and appetite and a major therapeutic target for type 2 diabetes (T2D) and obesity. Genetic studies have implicated the GLP1R locus in both body mass index (BMI) and T2D, but it remains unclear whether their underlying genetic associations are the same. Methods: We analyzed 431,107 participants of genetically inferred European ancestry from the Million Veteran Program. Within 500 kb of GLP1R, we performed locus-wide linear regression models for BMI and logistic regression models for T2D, adjusted for age, sex, and 10 principal components. We identified primary and secondary BMI sentinel variants using conditional analyses and evaluated their associations with T2D. Bayesian fine-mapping was used to construct credible sets of GLP1R locus for BMI and T2D. Results: Conditioning on the primary sentinel variant rs12213929 (upstream of GLP1R, {beta} = 0.11; 95% CI 0.09-0.14; p = 1.94E-17), we identified a secondary variant (rs13216992, intron of GLP1R) independently associated with BMI ({beta} = 0.10; 95% CI 0.07-0.13; p = 7.88E-14). The two sentinel variants showed low linkage disequilibrium (r2 = 0.03). A two-variant allelic burden score (0-4; sum of the rs12213929 G-allele count and rs13216992 C-allele count) showed that participants with 4 risk alleles had 0.47 kg/m2 higher BMI than those with 0 risk alleles (95% CI 0.39-0.55; p < 2E-16). Both variants were associated with higher T2D risk, but with distinct patterns after BMI adjustment: the rs12213929-T2D association persisted after adjustment for BMI (OR = 1.02; 95% CI 1.01-1.03; p = 0.0004), whereas the rs13216992-T2D association was fully attenuated (OR = 1.00; 95% CI 0.99-1.01; p = 0.68). Fine-mapping identified a compact 95% BMI credible set of 17 variants and a broader 95% T2D credible set of 42 variants, with all BMI credible variants contained within the T2D set. Conclusions: The GLP1R locus harbors at least two independent BMI-associated variants that exhibit heterogeneous relationships with T2D: rs12213929 influences T2D risk partly through BMI-independent pathways, whereas rs13216992 appears to act predominantly via adiposity. These findings refine the genetic architecture at this key therapeutic target gene and provide a foundation for functional and pharmacogenomic studies to determine whether GLP1R variation can inform precision prevention and treatment of obesity and T2D.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human cancers. The current largest published PDAC Genome-Wide Association Study (GWAS) identified 23 genetic risk signals, but most lack sufficient characterization. This study aimed to functionally characterize the chr13q12.2 (PLUT/PDX1) PDAC GWAS risk locus. Fine-mapping, luciferase reporter assays, and electrophoretic mobility shift assays implicated rs9581943, a PDX1 promoter SNP, as a functional variant underlying this GWAS signal. GTEx expression QTL analyses identified rs9581943 as a significant PDX1 eQTL in pancreas, and CRISPR/Cas9 editing in PDAC-derived cell lines confirmed a functional relationship. PDX1 is a transcription factor involved in early pancreas development and {beta}-cell homeostasis, but its role in exocrine pancreatic cells is unclear. Single-nucleus RNA-seq analyses of pancreatic acinar and ductal cells from neonatal, adult, and chronic pancreatitis donors suggested PDX1 activity alleviates high secretory load and ER-stress in acinar and biases ducts toward homeostatic phenotypes. Similarly, scRNA-seq analyses of pancreatic tumors suggested PDX1 activity reduces biosynthetic and inflammatory stress and promotes epithelial differentiation. Our study therefore implicates rs9581943 as a causal variant for the chr13q12.2 PDAC GWAS signal wherein the risk allele reduces PDX1 expression, eroding PDX1's capacity to buffer stress and stabilize epithelial cell fate in the exocrine compartment.

Dietary patterns worldwide have shifted toward increased consumption of ultraprocessed foods (UPFs), which has been linked to higher disease burden. One mechanism proposed to impact both their consumption and contribution to metabolic disease is altered post-ingestive metabolic response in comparison to nutritionally similar foods. Here, we recruited 57 healthy-weight 18-45-year-old adults to examine the effects of food processing on postprandial metabolism and brain response. Despite nutritional matching, UPF meals evoked a greater insulinemic and energetic response with attenuated carbohydrate oxidation relative to non-UPF meals. Next, between-condition differences in peak carbohydrate oxidation were associated with mesolimbic and superior temporal gyrus activation in response to food cues. Finally, although food value did not differ between conditions, brain responses correlated with food valuation were positive for non-UPF but negative for UPF in visual cortex and striatum. These findings demonstrate that food processing influences post-ingestive metabolism in a way that could help explain long term health effects and differences in food reward through mechanisms beyond calories and macronutrient composition alone.

Importance Women have been under-represented in clinical trials of type 2 diabetes mellitus (T2D), and evidence on sex differences in effectiveness of T2D treatments remains limited. Objective To assess sex differences in comparative effectiveness and safety of four second-line antidiabetic agents: glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and sulfonylureas (SU). Design Retrospective cohort study using an active-comparator new-user design, following each participant till treatment discontinuation or end of data. Setting Multinational study across ten real-world databases from the Observational Health Data Sciences and Informatics (OHDSI) network in the United States, United Kingdom, Germany, and Spain. Participants 5.15 million adults with T2D who initiated one of the four second-line therapies following metformin during 1992-2021. Exposures GLP-1RA, SGLT2i, DPP4i, or SU. Main Outcomes and Measures Cardiovascular effectiveness as measured through 7 outcomes (major adverse cardiovascular events and glycemic control) and safety through 18 outcomes as highlighted by ADA guideline. Hazard ratios (HRs) are estimated separately for women and men using propensity score-stratified Cox models with empirical calibration. Sex differences were tested using Z-tests on log-HR differences. Results Drug initiation rates differed by sex with 9.28% of women initiating on GLP-1RA, 11.91% SGLT2i, 27.81% DPP4i, and 50.99% SU; the rates among the men were 5.41%, 12.84%, 24.64%, and 57.10%. No significant sex differences were observed for cardiovascular effectiveness outcomes. Several safety outcomes showed significant sex differences that are consistent across drug comparisons. Focusing on GLP-1RA compared to SGLT2i for brevity, GLP-1RA users experienced the following comparative benefits and risks: higher risk of acute pancreatitis among women (HR 1.39 [1.13, 1.70]) while non-differential risk among men (HR 0.91 [0.74, 1.12]) with p = 0.005 for the test of difference; non-differential risk of hypotension among women (HR 1.08 [0.98, 1.19]) while lower risk among men (HR 0.87 [0.78, 0.96]) with p = 0.003. Where no sex differences were found, our findings were consistent with existing evidence. Conclusions and Relevance This large-scale multinational study on antidiabetic agents identified clinically relevant sex differences, which are biologically plausible but previously lacked clinical evidence. Our findings reinforce the importance of tailoring T2D management according to sex.

The transcription coregulator OCA-B promotes CD4+ T cell memory recall responses and autoimmunity. OCA-B T cell deletion prevents spontaneous type-1 diabetes (T1D) onset in non-obese diabetic (NOD) mice and blunts T1D in a subset of more aggressive models. However, the role of OCA-B in diabetes induced by treatment with immune checkpoint inhibitors (ICIs), and the role of OCA-B in the control of tumors with and without ICI treatment, has not been studied. Here we show that islet and pancreatic lymph node T cells from T1D individuals express measurable POU2AF1 mRNA. Deletion of OCA-B in T cells fully insulates 8-week-old non-obese diabetic (NOD) mice against ICI-induced diabetes and partially protects 12-week-old mice. Salivary and lacrimal gland infiltration and inflammation were also reduced. Protection was associated with a block in the differentiation of progenitor exhausted CD8+ T cells (TPEX) into terminally exhausted CD8+ T cells (TEX). We show that OCA-B T cell loss preserves anti-tumor immune responses following PD-1 blockade in different tumors and mouse strains. These findings point to a potential therapeutic window in which pharmaceuticals targeting OCA-B could be used to block the emergence of both spontaneous and ICI-induced autoimmunity while sparing anti-tumor immunity. We develop first-in-class small molecule inhibitors of Oct1/OCA-B transcription complexes and show that administration into NOD mice also blocks diabetes emergence following PD-1 blockade. These results identify OCA-B as a promising therapeutic target for the prevention of autoimmunity and immune-related adverse events (irAEs).

The modern Western diet (MWD) provides high linoleic acid (LA) exposure, typically contributing 6-9% of total caloric intake. These high LA levels have fueled a longstanding debate regarding whether this dietary pattern confers benefit or risk. Importantly, LA intake is disproportionately elevated among lower socioeconomic populations due to greater reliance on industrial seed oils and ultra-processed foods. Despite decades of research, controlled dietary intervention studies directly evaluating the biological consequences of varying LA exposure remain limited. The current randomized, double-blind intervention compared the effects of a 12-week Low LA diet (2.5% energy) versus a High LA diet (10.0% energy) in healthy adults. Primary outcomes included plasma highly unsaturated fatty acid (HUFA) concentrations and ex vivo zymosan-stimulated whole-blood oxylipin generation. Fifty- two participants completed the intervention. High LA exposure resulted in a marked reduction in plasma n-3 eicosapentaenoic acid (EPA) concentrations compared with the LowLA arm. In contrast, levels of arachidonic acid (ARA), dihomo-gamma-linolenic acid (DGLA) and docosahexaenoic acid (DHA) did not differ by dietary LA exposure. Analysis of oxylipin species revealed that levels of EPA-derived relative to ARA-derived mediators were significantly reduced in the High LA arm. These findings reveal that higher dietary LA selectively suppresses EPA pools and EPA-derived oxylipins without altering ARA, shifting the lipid mediator balance toward a more n-6-dominant profile.

Chronic wounds, such as diabetic and ischemic ulcers, involve impaired perfusion and delayed healing. TOP-N53 is a novel bifunctional molecule combining nitric oxide (NO) release with phosphodiesterase-5 (PDE5) inhibition to enhance local NO-cGMP signalling, resulting in vasodilation and angiogenesis. This first-in-human, randomized, double-blind, vehicle-controlled Phase I trial assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single subcutaneous TOP-N53 doses in 29 healthy male volunteers. Each participant received injections of TOP-N53 and vehicle in the same forearm, but either at the proximal or at the distal site in an intra-individually blinded manner. Safety assessments included local and systemic parameters. PK and PD responses were evaluated by analysis of TOPN53 and its bioactivation metabolite TOP-52 in plasma, and by Laser Speckle Contrast Imaging (LSCI), a non-invasive method to measure skin perfusion, respectively. TOP-N53 was safe and well tolerated, with no serious adverse events or local or systemic adverse reactions. Plasma concentrations remained below the quantification limit and LSCI showed sustained dose-dependent increases in local skin perfusion at doses of 4.84 ug and 9.075 ug TOP-N53 SC for up to 24 h post injection when compared to vehicle. These findings support the favourable safety and tolerability profile of TOP-N53 associated with locally improved skin perfusion, encouraging its further clinical development as a topical treatment for chronic wounds with microvascular dysfunction.

End-stage liver disease (ESLD) is one of the leading causes of death worldwide. Currently, the only curative option for patients with ESLD is liver transplantation. However, the demand for donor livers far exceeds the available supply, partly because many potentially viable livers are discarded following biopsy evaluation. While biopsy is the gold standard for assessing liver histological features related to graft quality and transplant suitability, it often leads to high discard rates due to its susceptibility to sampling errors and limited spatial coverage. Besides, biopsy is invasive, time-consuming, and unavailable in clinical facilities with limited resources. Here, we present an AI-assisted photoacoustic/ultrasound (PA/US) imaging framework for quantitative assessment of human donor liver graft quality and transplant suitablity at the whole-organ scale. With multimodal volumetric PA/US images as the input, our deep-learning (DL) model accurately predicted the risk level of fibrosis and steatosis, which indicate the graft quality and transplant suitability, when comparing with true pathological scores. DL also identified the imaging modes (PAI wavelength and B-mode USI) that correlated the most with prediction accuracy, without relying on ill-posed spectral unmixing. Our method was evaluated in six discarded human donor livers comprising sixty spatially matched regions of interest. Our study will pave the way for a new standard of care in organ graft quality and transplant suitability that is fast, noninvasive, and spatially thorough to prevent unnecessary organ discards in liver transplantation.

Systemic inflammation is implicated in various diseases, yet its upstream determinants remain poorly examined. We conducted a large scale two-sample Mendelian randomisation (MR) study to systematically evaluate the potential causal effects of 3,213 molecular (metabolomic, proteomic), physiological and disease traits on circulating interleukin-6 (IL-6) and C-reactive protein (CRP) levels. Genetic instruments were derived from genome wide association studies and analysed using inverse variance weighted (IVW), weighted median, and MR-Egger methods with multiple testing correction. Bidirectional MR was performed to assess reverse causation. After Bonferroni correction, evidence of potential causal effects was observed for 72 traits on CRP and 9 traits on IL-6. CRP was predominantly influenced by metabolomic traits, especially lipid and fatty acid measures. Genetically proxied adiposity (body mass index and obesity), triglyceride rich lipoproteins, glycoprotein acetyls (GlycA), and apolipoprotein E increased CRP levels, whereas HDL-related cholesterols, polyunsaturated fatty acids, and glutamine decreased CRP. Most associations were consistent across MR methods, supporting the robustness of these results. As expected, IL-6 had a large effect on CRP. IL-6 was influenced by primarily adiposity and HDL-related lipid measures, with generally smaller effect sizes and limited support across sensitivity analyses. Bidirectional analyses indicated little evidence that CRP directly drives metabolic traits when restricting to cis-acting instruments, whereas genetically proxied IL-6 signalling showed consistent downstream effects on HDL particle concentration and composition. Adiposity is a shared upstream determinant of both inflammatory biomarkers, with stronger and broader effects on CRP. These findings suggest that CRP acts as an integrated downstream readout of systemic inflammatory burden, whereas IL-6 reflects a more tightly regulated and context-dependent process. Our work clarifies traits that may causally influence systemic inflammation and highlights biological pathways linking inflammation to cardiometabolic and inflammatory diseases. By mapping upstream determinants of IL-6 and CRP, we also provide a resource to prioritise key drivers for mechanistic study and therapeutic targeting.

AimWe examined associations between smoking and HbA1c among U.S. adults, and whether these associations vary by diabetes status. MethodsWe analyzed NHANES data from 2015-2018 for adults aged [&ge;]20 years. Smoking was assessed by self-report and serum cotinine. Survey-weighted multivariable linear regression was used to evaluate the association between smoking and HbA1c in the full population (N=9,214) and in adults without diabetes (N=7,328), adjusting for demographics, blood pressure, waist circumference, lipids, and C-reactive protein. ResultsAfter adjustment for cardiometabolic covariates, there was no significant association between smoking and HbA1c in the full population (former: {beta}=0.029%, p=0.30; current: {beta}=0.053%, p=0.13). Among adults without diabetes, former smoking was not associated with HbA1c, whereas current smoking remained significantly associated (former: {beta}=-0.001%, p=0.923; current: {beta}=0.067%, p<0.001). These findings were similar when cotinine was used as the exposure measure, with active smoking ([&ge;]3.0 ng/mL) associated with higher HbA1c among non-diabetic adults (p<0.001), but not in the full population. ConclusionsAmong adults without diabetes, current but not former smoking was associated with higher HbA1c. The absence of an association in former smokers suggests that this effect may attenuate following cessation. These findings support early cessation interventions and may inform cessation counseling and diabetes screening.

How embryonic cells generate large clones of cells in the adult represents a fundamental question in biology. Here, using melanocyte stem cells (McSCs) in the zebrafish as a model, we explore the function of the master melanocyte transcription factor (MITF) in safeguarding McSCs in embryonic development and their potential to pigment large clones in the adult. MITF is well known is for its role in the specification of melanoblasts from the neural crest (NC) and their differentiation into melanocytes, yet little is known about how this activity shapes the stem cell lineages. Here, we use live imaging coupled with single-cell transcriptomics and lineage tracing to show that MITF (mitfa in zebrafish) protects the melanocyte stem cell (McSC) fate in zebrafish. Utilizing a temperature sensitive mitfavc7 mutant, we show loss of Mitfa leads to a surprising premature and aberrant expansion of McSC progeny at the niche during embryogenesis, coupled with novel emergent transcriptional cell states. Linage tracing of McSCs from the embryonic to juvenile stages reveals Mitfa activity is subsequently required in regeneration by Schwann cell-like and melanocyte stem cell progenitors that serve as a reservoir for fast-responding pigment progenitors. Thus, the impact of Mitfa loss on the melanocyte lineage is cell-state and stage-specific. The emergent cell states upon mitfa loss may have important implications for our understanding the loss of MITF activity in human genetic disease and melanoma.

Female genital tract (FGT) polyps are common benign growths affecting up to half of all women. However, they carry malignant potential, and their genetic architecture remains poorly defined. We conducted a genome-wide association study (GWAS) meta-analysis across four biobanks (48,400 cases, 477,134 controls), identifying 26 risk loci for FGT polyps, 12 of which were previously unreported. Integrative gene prioritisation highlighted 193 candidate genes, revealing a potential convergent biological mechanism: where germline variation in DNA replication and maintenance (e.g., PRIM1, TERT and HMGA1) compromises genomic stability in the context of hormone-driven proliferation (e.g., ESR1 and GREB1). This susceptibility is further modulated by metabolic drivers of estrogen biosynthesis, underscored by specific adiposity-related loci (e.g. RSPO3 and PLCE1) and the aromatase gene CYP19A1. Mendelian randomisation demonstrated bidirectional causal relationships with endometriosis and fibroids, and endometrial cancer. Leveraging the shared genetic architecture of FGT polyps and other gynaecological disorders via multi-trait analysis revealed an additional 26 loci, validating sub-threshold regions encompassing HMGA1 and GREB1. In total, 52 risk loci were identified (36 novel), 39 of which replicated in an independent cohort. These findings reframe polyps not merely as local gynaecological overgrowths but as manifestations of a systemic proliferative syndrome characterised by dysregulated genome stability and estrogen signalling, which may also impact malignant transformation.

BackgroundAccelerometer-derived behavioral phenotype captures multidimensional aspects of human behavior extending well beyond physical activity, encompassing light exposure, step counts, physical activity patterns, sleep, and circadian rhythms. Whether these five domains constitute a unified behavioral architecture underlying cancer risk and whether circadian organization and light exposure confer incremental predictive value beyond movement volume alone remains to be comprehensively established. MethodsWe conducted an accelerometer-wide association study (AWAS) encompassing the complete accelerometer-derived behavioral exposome across five behavioral domains in UK Biobank participants with valid wrist accelerometry data. Incident solid cancers were designated as the primary endpoint, with prespecified site-specific solid cancers and hematological malignancy as secondary outcomes. Cox proportional hazards models with age as the timescale were used. The minimal covariate set served as the primary reporting tier, followed by sensitivity analyses additionally adjusting for adiposity/metabolic factors, independent activity patterns, shift work history, and accelerometry measurement quality. Nominal statistical significance was defined as two-sided P < 0.05 ResultsAmong 89,080 participants, 6,598 incident solid cancer events were observed over a median follow-up of 8.39 years. In the minimally adjusted model, the pan-solid-tumor association atlas was dominated by signals from activity volume, inactivity fragmentation, and circadian rhythm. Higher overall acceleration (HR per SD: 0.91, 95% CI: 0.89-0.94) and higher daily step counts (HR: 0.93, 95% CI: 0.90-0.95) were independently associated with reduced solid cancer risk, while inactivity fragmentation metrics were consistently linked to higher risk. Notably, circadian rhythms, most prominently cosinor mesor (Midline Estimating Statistic of Rhythm under cosinor model), emerged as leading inverse risk signals, underscoring the independent contribution of circadian behavioral architecture. Site-specific analyses revealed pronounced heterogeneity across tumor sites. Lung cancer exhibited a robust inverse activity-risk gradient, while breast cancer showed reproducible associations with MVPA. Most strikingly, nocturnal light exposure demonstrated a tumor-site-specific association confined to pancreatic cancer, a signal absent across all other sites examined. Associations for uterine cancer were predominantly inactivity-related and substantially attenuated following adjustment for adiposity and metabolic factors. ConclusionsAcross five accelerometer-derived behavioral domains, solid cancers as a whole were most consistently associated with a high-movement, low-fragmentation, and circadian-coherent behavioral profile. While site-specific heterogeneity exists, the broad cancer risk landscape is dominated by movement volume, inactivity fragmentation, and circadian rhythmicity. Light exposure, although more localized in its contribution, demonstrates a potentially novel and specific association with pancreatic cancer risk. These findings support a five-domain behavioral exposome framework for cancer epidemiology and, importantly, position circadian rhythm integrity and nocturnal light exposure as critically understudied dimensions warranting dedicated mechanistic investigation.

Background and aims: Pancreatic ductal adenocarcinoma (PDAC) surveillance is limited to individuals with familial or genetic risk although most future cases arise outside these groups. In a retrospective study, PRISM, an electronic health record (EHR)-based PDAC risk model, identified individuals in the general population at elevated near-term risk of PDAC. We aimed to prospectively evaluate whether PRISM can identify high-risk individuals beyond current surveillance groups across U.S. health systems. Methods: We performed a prospective multicenter cohort study after deployment of PRISM in April 2023 across 44 U.S. health care organizations. Eligible adults aged [&ge;]40 years without prior PDAC received a single baseline risk score and were assigned to prespecified risk tiers. Patients were followed for incident PDAC for 30 months. We estimated tier-specific 30-month cumulative incidence (positive predictive value, PPV), number needed to screen (NNS), standardized incidence ratios (SIRs), and time from deployment and first high-risk flag to diagnosis. Results: Among 6,282,123 adults assigned a PRISM score, 5,058,067 had follow-up; 3,609 developed PDAC. The highest-risk tier had 30-fold higher PDAC incidence than the study population. At the SIR 5 threshold, 30-month cumulative incidence was 0.35% (NNS, 284.2); at SIR 16, 1.14% (NNS, 87.4); and at SIR 30, 2.19% (NNS, 45.7). Median time from deployment to PDAC diagnosis was 9.5 months, and median time from first high-risk flag to diagnosis at SIR 5 was 3.5 years. Shapley additive explanations (SHAP) analyses supported patient- and tier-level interpretability. Conclusions: Prospective deployment of PRISM across multiple U.S. health care organizations identified individuals at elevated near-term risk for PDAC, with substantial risk enrichment and lead time before diagnosis. These findings support the real-world scalability and generalizability of EHRbased risk stratification for risk-adapted early detection. ClinicalTrials.gov identifier NCT05973331

Colorectal cancer (CRC) is the second leading cause of cancer death globally and the number one cause of cancer death in people under 50 years old. The reasons for the rise of early-onset CRC are unknown, and while anatomically distinct subtypes of CRC have substantial clinical and molecular associations, the etiology of region-specific disease, such as early-onset CRC's enrichment in the distal colon, remains unclear. Understanding regional mutagenesis may identify risk factors for this public health concern and CRC more broadly. To evaluate mutational dynamics across the premalignant colon, we performed whole-genome sequencing of 125 individual colon crypts taken from six standardized regions biopsied during colonoscopy, collected from 11 donors without polyps and 10 with polyps. We observed mutation spectra and accumulation rates consistent with previous whole-organ studies, with greater subclonal mutation capture enabled by experimental design. T>[A,C,G] mutations, which are associated with colibactin genotoxicity from pks+ Escherichia coli, were significantly enriched in the rectum of donors with and without polyps (adjusted p-values < 0.01). Moreover, when comparing findings to crypts from individuals with CRC and sequenced CRC tumors, we observed consistent enrichment of the colibactin-associated mutational signature "ID18" in the rectum in both normal colon crypts and CRC tumors, without significant difference in colibactin-specific single nucleotide variant or insertion-deletion burden in crypts across the three clinical groups (i.e., no polyp, polyp, and CRC). These findings argue against a causal or prognostic role for colibactin in CRC, instead indicating that the proposed association with early-onset disease reflects anatomic specificity rather than cancer-specific clinical relevance.

Altered iron homeostasis has long been implicated in Parkinson's Disease (PD), although the mechanisms have not been clear. Given the critical role of PD-related activating mutations in LRRK2 (leucine-rich repeat protein kinase 2) within membrane trafficking pathways we examined the impact of a homozygous mutant LRRK2G2019S on iron homeostasis within the RAW macrophage cell line with high iron capacity. Proteomics analysis revealed a dysregulation of iron-related proteins in steady state with highly elevated levels of ferritin light chain and a reduction of ferritin heavy chain. LRRK2G2019S mutant cells showed efficient ferritinophagy upon iron chelation, but upon iron overload there was a near complete block in the degradation of the ferritinophagy adaptor NCOA4. These conditions lead to an accumulation of phosphorylated Rab8 at the plasma membrane, which is selectively inhibited by LRRK type II kinase inhibitors. Iron overload then leads to increased oxidative stress and ferroptotic cell death. These data implicate LRRK2 as a key regulator of iron homeostasis and point to the need for an increased focus on the mechanisms of iron dysregulation in PD.