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