Frances M. Sladek

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well‐structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point‐in‐time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70232 . The Concise Guides provide expert‐curated recommendations of ‘Gold Standard’ selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid‐2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. Nuclear hormone receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, catalytic receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries information of the best available pharmacological tools, key references, and suggestions for further reading.

The nomenclature of hepatocyte nuclear factor-4 receptors is agreed by the NC-IUPHAR Subcommittee on Nuclear Hormone Receptors [9, 3]. While linoleic acid has been identified as the endogenous ligand for HNF4α its function remains ambiguous [80]. HNF4γ has yet to be paired with an endogenous ligand.

Hepatocyte nuclear factor 4 alpha (HNF4α), cloned over 30 years ago based on its ability to bind a couple of DNA elements in liver-specific genes, is now considered to be the master regulator of liver-specific transcription. HNF4α is also expressed in several other tissues, including intestines, kidney, stomach and pancreas, and is linked to several human diseases (Figure 1). As a member of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors, HNF4α has two highly conserved domains for DNA binding (DBD) and ligand binding (LBD) and binds DNA as a homodimer. This Research Topic contains four reviews and three original research articles covering some of the most important areas of research on HNF4α and its paralog HNF4γ. The original research article by Deans et al uses the exon swap mice to elucidate the role of P2-versus P1-HNF4α isoforms in the adult liver. P2-HNF4α was originally identified in an embryonic cancer cell line but is now known to be expressed in the normal adult liver during periods of fasting, high fat diet and alcohol-associated liver disease, as well as liver cancer. The authors use multiple 'omics approaches to show not only that HNF4α is one of the most highly expressed transcription factors in the adult liver but also that the hundreds of genes uniquely regulated by P2-HNF4α (including several cytochrome P450 genes) are consistent with a role in metabolism. They show that the differential gene expression is likely due to interactions with coregulators rather than alterations in DNA or chromatin binding and propose a potential role for the HNF4α isoforms in the circadian switch between carbohydrate and lipid metabolism.The review by Vemuri et al focusses on the intestines which express both P1-and P2-HNF4α as well as HNF4γ. HNF4α binds DNA as a homodimer and cannot heterodimerize with other NRs, with the exception of HNF4γ. Like HNF4α, HNF4γ has been shown to bind fatty acids although, as with HNF4α, the role of ligand binding in receptor function is not clear. Both HNF4 genes play a key role in intestinal maturation, differentiation and regeneration as well as stem cell renewal (via fatty acid oxidation) and barrier function, allowing for one paralog to compensate for the loss of the other. HNF4α intersects with the immune system in multiple ways and, along with HNF4γ, protects against a chronic inflammatory state in the gut. Both HNF4 genes are implicated in the intestinal entry of SARS-CoV2 via regulation of the Ace2 and Tmprss2 genes in the intestinal epithelium. Interestingly, three distinct high fat diets have also been shown to alter the expression of these (and other) COVID-related genes as well as Hnf4a in the mouse intestines (1).The original article by Kotulkar et al explores the interaction between HNF4α and the protooncogene c-Myc in liver regeneration after partial hepatectomy. Deletion of HNF4α increases the expression of c-Myc and cyclin D1 (Ccnd1) while the double knockout of HNF4α and c-Myc decreases hepatocyte proliferation demonstrating that HNF4α is critical for both termination of liver regeneration and survival after partial hepatectomy. Another intriguing observation is the emergence of HNF4α+ hepatocytes in HNF4α knockout mice, presumably from the cholangiocytes. This work highlights a role for HNF4α in regulating cell proliferation, as well as basic metabolism.Critical areas of future HNF4 research include the role of: i) HNF4α in the intersection between cell metabolism and proliferation; ii) the different splice variants and the factors that regulate splicing as well as the alternate HNF4A promoters; iii) post translational modifications (PMTs) in HNF4 and how they can be impacted by SNPs in the human population (2); iv) HNF4α versus HNF4γ in the intestines (and other tissues), including homo-versus heterodimers and their interaction with the microbiome (3); v) the incredible diversity of HNF4 and other NR binding motifs and how those might be impacted by SNPs (4); vi) the function of HNF4 in tissues outside of the liver and intestines and interorgan crosstalk with non expressing tissues such as adipose (5,6); vii) ligand binding and identification of additional ligands, including potential therapeutic drugs; and viii) HNF4 in xenobiotic and drug metabolism (7). Finally, given the ancient origins of HNF4, it will be important to continue exploring new ways in which this 'old' receptor acts in all animal organisms.

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4α we show that this isoform orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions, including with different clock proteins at different times of the day leading to subtle differences in circadian gene regulation. Furthermore, deletion of the Clock gene alters the circadian oscillation of P2- (but not P1-)HNF4α RNA, revealing a complex feedback loop between the HNF4α isoforms and the hepatic clock. Finally, we demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in female mice. Taken together, we propose that the highly conserved two-promoter structure of the Hnf4a gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.

Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, and the most common primary liver malignancy to present in the clinic. With the exception of liver transplant, treatment options for advanced HCC are limited, but improved tumor stratification could open the door to new treatment options. Previously, we demonstrated that the circadian regulator Aryl Hydrocarbon‐Like Receptor Like 1 (ARNTL, or Bmal1 ) and the liver‐enriched nuclear factor 4 alpha (HNF4α) are robustly co‐expressed in healthy liver but incompatible in the context of HCC. Faulty circadian expression of HNF4α– either by isoform switching, or loss of expression‐ results in an increased risk for HCC, while BMAL1 gain‐of‐function in HNF4α‐positive HCC results in apoptosis and tumor regression. We hypothesize that the transcriptional programs of HNF4α and BMAL1 are antagonistic in liver disease and HCC. Here, we study this antagonism by generating a mouse model with inducible loss of hepatic HNF4α and BMAL1 expression. The results reveal that simultaneous loss of HNF4α and BMAL1 is protective against fatty liver and HCC in carcinogen‐induced liver injury and in the “STAM” model of liver disease. Furthermore, our results suggest that targeting Bmal1 expression in the absence of HNF4α inhibits HCC growth and progression. Specifically, pharmacological suppression of Bmal1 in HNF4α‐deficient, BMAL1‐positive HCC with REV‐ERB agonist SR9009 impairs tumor cell proliferation and migration in a REV‐ERB‐dependent manner, while having no effect on healthy hepatocytes. Collectively, our results suggest that stratification of HCC based on HNF4α and BMAL1 expression may provide a new perspective on HCC properties and potential targeted therapeutics.

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2- HNF4α is expressed at ZT9 and ZT21 in the normal adult liver and orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions. We demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in females. Exon swap mice expressing only P2- HNF4α exhibit subtle differences in circadian gene regulation and disruption of the clock increases expression of P2-HNF4α. Taken together, we propose that the highly conserved two-promoter structure of the Hnfa gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.

Soybean oil consumption has increased greatly in the past half-century and is linked to obesity and diabetes. To test the hypothesis that soybean oil diet alters hypothalamic gene expression in conjunction with metabolic phenotype, we performed RNA sequencing analysis using male mice fed isocaloric, high-fat diets based on conventional soybean oil (high in linoleic acid, LA), a genetically modified, low-LA soybean oil (Plenish), and coconut oil (high in saturated fat, containing no LA). The 2 soybean oil diets had similar but nonidentical effects on the hypothalamic transcriptome, whereas the coconut oil diet had a negligible effect compared to a low-fat control diet. Dysregulated genes were associated with inflammation, neuroendocrine, neurochemical, and insulin signaling. Oxt was the only gene with metabolic, inflammation, and neurological relevance upregulated by both soybean oil diets compared to both control diets. Oxytocin immunoreactivity in the supraoptic and paraventricular nuclei of the hypothalamus was reduced, whereas plasma oxytocin and hypothalamic Oxt were increased. These central and peripheral effects of soybean oil diets were correlated with glucose intolerance but not body weight. Alterations in hypothalamic Oxt and plasma oxytocin were not observed in the coconut oil diet enriched in stigmasterol, a phytosterol found in soybean oil. We postulate that neither stigmasterol nor LA is responsible for effects of soybean oil diets on oxytocin and that Oxt messenger RNA levels could be associated with the diabetic state. Given the ubiquitous presence of soybean oil in the American diet, its observed effects on hypothalamic gene expression could have important public health ramifications.

Soybean oil consumption is increasing worldwide and parallels a rise in obesity. Rich in unsaturated fats, especially linoleic acid, soybean oil is assumed to be healthy, and yet it induces obesity, diabetes, insulin resistance, and fatty liver in mice. Here, we show that the genetically modified soybean oil Plenish, which came on the U.S. market in 2014 and is low in linoleic acid, induces less obesity than conventional soybean oil in C57BL/6 male mice. Proteomic analysis of the liver reveals global differences in hepatic proteins when comparing diets rich in the two soybean oils, coconut oil, and a low-fat diet. Metabolomic analysis of the liver and plasma shows a positive correlation between obesity and hepatic C18 oxylipin metabolites of omega-6 (ω6) and omega-3 (ω3) fatty acids (linoleic and α-linolenic acid, respectively) in the cytochrome P450/soluble epoxide hydrolase pathway. While Plenish induced less insulin resistance than conventional soybean oil, it resulted in hepatomegaly and liver dysfunction as did olive oil, which has a similar fatty acid composition. These results implicate a new class of compounds in diet-induced obesity–C18 epoxide and diol oxylipins.