Mendelian randomization linking metabolites with enzymes reveals pathway regulation and therapeutic avenues

Adriaan van der Graaf  ¹ , Sadegh Rizi  ² , Chiara Auwerx  ³ , Zoltán Kutalik  ⁴

Affiliations

• PMID: 41650937
• DOI: 10.1016/j.ajhg.2025.12.013

Abstract

Reactions between metabolites are catalyzed by enzymes. These biochemical reactions form complex metabolic networks, which are only partially characterized in humans and whose regulation remains poorly understood. Here, we assess human biochemical reactions and regulation using Mendelian randomization (MR), a genetic observational causal inference technique, to understand the methods’ strengths and weaknesses in identifying metabolic reactions and regulation. We combine four metabolite and two protein quantitative trait locus (QTL) studies to determine how well MR recovers 945 curated canonical enzyme-substrate/product relationships. Using genetic variants from an enzyme’s transcribed (cis) region as instrumental variables, MR-inferred estimates have high precision (35%-47%) but low recall (3.2%-4.6%) for identifying the substrates and products of an enzyme. Testing reverse causality from metabolites to enzymes using genome-wide instruments yields lower precision (1.8%-8.5%) and recall (1.0%-1.9%) due to an increased multiple-testing burden. Literature review of 106 Bonferroni-significant results identifies 45 links (43%) confirmed by different degrees of evidence, including bidirectional links between linoleate and cytochrome P450 3A4 (CYP3A4) levels (p = 8.6 × 10^-32). Eleven enzymes in the 106 links involve drug targets, allowing for an interpretation between N-acetyl putrescine and IL1RAP (p = 2.7 × 10^-7), as IL1RAP is a target of the psoriasis drug spesolimab, and putrescine levels are elevated in psoriatic tissues. This work highlights how MR can be leveraged to explore human metabolic regulation and identify both canonical reactions and previously unknown regulation.

The HCF-1:OGT axis regulates neuronal proliferation and differentiation

Ayushma  ¹ , Priyanka Prakash Srivastava  ¹ , Shruti Kaushal  ² , Jaspreet K Dhanjal  ² , Vaibhav Kapuria  ³ , Shilpi Minocha  ⁴

Affiliations

• PMID: 41651253
• DOI: 10.1016/j.nbd.2026.107308

Free article

Abstract

Neuronal differentiation requires precise coordination of progenitor proliferation, lineage commitment, and chromatin regulation to establish functional brain architecture. Host Cell Factor-1 (HCF-1), an X-linked transcriptional co-regulator linked to human intellectual disability, is essential for early development, yet its lineage-specific roles during mammalian neurogenesis remain incompletely defined. Here, we investigate the function of the HCF-1-OGT axis during neuronal differentiation and forebrain development. Early embryonic loss of HCF-1 resulted in developmental arrest due to gastrulation defects, while conditional deletion in Nkx2.1-derived neuronal lineages caused pronounced cortical disorganization, reduced GABAergic interneuron survival, and severe defects in forebrain commissures, including the corpus callosum and anterior commissure. These abnormalities were not observed following glial-restricted deletion, indicating a neuron-specific requirement for HCF-1. Neuronal ablation alone did not phenocopy these defects; however, combined neuronal ablation and HCF-1 loss exacerbated cortical and commissural abnormalities, revealing increased neuronal vulnerability. Transcriptomic profiling following HCF-1 depletion identified widespread dysregulation of gene networks associated with neuronal differentiation, synaptic organization, chromatin regulation, and axon guidance. Consistently, HCF-1 directly occupied promoters of key neuronal genes, including Elavl3 and NeuroD1, and its loss reduced activating chromatin marks at these loci. In vitro, depletion of HCF-1 or inhibition of OGT impaired neuronal proliferation, differentiation, and neurite outgrowth. Glycoproteomic analysis further revealed disruption of OGT-dependent protein networks involved in neuronal structure and maturation. Together, these findings identify HCF-1 as a central regulator of neuronal differentiation and forebrain organization and provide mechanistic insight into how disruption of the HCF-1-OGT axis contributes to neurodevelopmental disorders.

PPARβ/δ contributes to the antidiabetic effect and the increase in GDF15 caused by metformin

Javier Jurado-Aguilar  ^{1   2   3   4} , Emma Barroso  ^{1   2   3   4} , Patricia Rada  ^{3   5} , Mona Peyman  ^{1   2   3   4} , Adel Rostami  ^{1   2   3   4} , Jesús Balsinde  ^{3   6} , Ángela M Valverde  ^{3   5} , Walter Wahli  ^{7   8} , Xavier Palomer  ^{1   2   3   4} , Manuel Vázquez-Carrera  ^{9   10   11   12}

Affiliations

• PMID: 41545750
• DOI: 10.1038/s41401-025-01705-5

The dynamics of mutational selection in cutaneous squamous carcinogenesis

Greta Skrupskelyte  ¹ , Joanna C Fowler  ² , Stefan Dentro  ^{2   3   4} , Carine Winkler  ⁵ , Irina Abnizova  ² , Niklaus Beumer  ^{3   6   7} , Roshan Sood  ² , Thomas Quarrell  ⁸ , Charlotte King  ² , Jivko Kamarashev  ⁹ , Emmanuella Guenova  ^{10   11} , Moritz Gerstung  ^{3   4} , Benjamin A Hall  ¹² , Liliane Michalik  ⁵ , Philip H Jones  ^{13   14}

• PMID: 41526710
• DOI: 10.1038/s42003-025-09406-9

Abstract

Identifying the mutant genes that are selected during carcinogenesis is key to identifying candidates for intervention and understanding the processes that promote transformation. Here we applied two selection metrics to study the dynamics of mutational selection in a mouse model of ultraviolet light driven skin carcinogenesis in which multiple synchronous tumors develop in each animal. Sequencing normal skin and tumors over a time course revealed two genetic routes to squamous carcinoma. Nonsynonymous Trp53 mutants were positively selected in both epidermis and tumors and present in 90% of tumors. The remaining tumors carried other oncogenic mutants, including activating Kras mutations. However, other positively selected mutant genes lost their competitive advantage in heavily mutated epidermis and in tumors. We found ten mutant genes under negative selection in normal skin, one of which was also negatively selected in tumors. In addition one gene was negatively selected in tumors but not normal skin. We conclude that analysing selection in normal tissue alongside tumors may resolve the dynamics of selection in carcinogenesis and refine the identification of cancer drivers.

Olfactory receptors: Making sense (and antisense) of monogenic expression

Richard Benton  ¹

• PMID: 41401789
• DOI: 10.1016/j.cub.2025.11.002

Abstract

Monogenic expression of odorant receptors (ORs) in individual sensory neurons is a hallmark of olfactory systems in insects and vertebrates. New studies highlight how transcriptional interference and antisense transcription might ensure such selectivity in large OR arrays of social insects.

Single nucleotide variants in UNC13C associated with neurodevelopmental disorders affect ethanol sensitivity in Drosophila

Franz Müller  ¹ , Sonja Neuser  ² , Gaurav Shrestha  ³ , Netra P Neupane  ⁴ , Katharina J Götze  ¹ , Nicola Brunetti-Pierri  ^{5   6   7} , Gaetano Terrone  ⁵ , Alexandre Reymond  ⁸ , Koen L van Gassen  ⁹ , Eva Brilstra  ⁹ , Katharina Steindl  ¹⁰ , Anais Begemann  ¹⁰ , Anita Rauch  ¹⁰ , Jonathan Rips  ¹¹ , Duha Fahham  ¹¹ , Tahsin Stefan Barakat  ¹² , Olivier Patat  ¹³ , Jérémie Mortreux  ¹⁴ , Matthew Hoi Kin Chau  ^{15   16   17} , Jill A Rosenfeld  ¹⁸ , Elizabeth Mizerik  ^{18   19} , Swati Srivastava  ^{18   20} , Xi Luo  ^{18   20} , Anne-Kristin Dahse  ¹ , Nicole Scholz  ¹ , Joydip Das  ⁴ , Gregg Roman  ²¹ , Tobias Langenhan  ^{1   22   23} , Rami Abou Jamra  ² , Achmed Mrestani  ^{1   24} , Dmitrij Ljaschenko  ¹

Affiliations

• PMID: 41399760
• PMCID: PMC12702192
• DOI: 10.1016/j.bbrep.2025.102375

Abstract

UNC13s are presynaptic proteins essential for neurotransmitter release at chemical synapses. In this study, we present eleven patients from nine families with severe neurodevelopmental impairments, who carry rare, biallelic UNC13C single-nucleotide variants (SNVs). Six missense variants, each identified in compound heterozygosity in one of three of these patients, were introduced into the Drosophila melanogaster ortholog unc13 using a previously established CRISPR/Cas9-based method for rapid and scarless genomic modifications, hypothesising that they underlie the observed clinical manifestations. However, none of the introduced mutations influenced Mendelian ratios, negative geotaxis, or lifespan of the fruit flies. Interestingly, two variants located outside the gene regions encoding known UNC13C domains caused a decreased ethanol sensitivity in Drosophila, while the Thr1729Met substitution within the C₁ domain resulted in increased ethanol sensitivity. Molecular dynamics simulations of the latter mutant gene product suggested that the altered protein conformation enhances exposure of the ethanol-binding site, thereby increasing sensitivity to ethanol. These findings reinforce previous evidence highlighting the critical role of the C₁ domain in ethanol sensitivity. Given the involvement of the C₁ domain in synaptic plasticity this result might implicate an influence of the Thr1729Met on synaptic function.

Keywords: Chemical synapse; Dunc13; Ethanol sensitivity; Molecular dynamics simulation; Neurodevelopmental disease; UNC13C; Unc13.

© 2025 The Authors.