Cystic echinococcosis is a zoonotic parasitic disease in which humans inadvertently become intermediate hosts of E. granulosus. After ingestion of parasite eggs, larvae migrate chiefly to the liver, where they develop into fluid-filled hydatid cysts that expand slowly over years. The disease is characterized by hepatic fibrosis and liver necrosis, and in endemic regions spanning Central Asia, the Middle East, South America and parts of China, it imposes a heavy burden of chronic illness. Surgery remains the definitive treatment for many patients, but drug therapy relies on a small arsenal of benzimidazole compounds that often achieve only parasitostatic rather than parasiticidal effects. The search for new molecular targets has therefore become a priority for parasitologists.

Ghrelin, an acylated peptide hormone discovered in 1999, is produced mainly by the stomach and acts through its receptor GHSR, a G protein-coupled receptor distributed throughout the central nervous system and peripheral tissues. Beyond stimulating appetite and growth hormone release, ghrelin has been implicated in inflammation, cell proliferation and fibrogenesis in the liver. Previous work by some of the same investigators had shown that ghrelin and GHSR regulate the progression of hepatic E. granulosus infection, and that genetic knockout of the GHSR gene inhibits disease progression in mice. What remained unclear was the precise mechanism by which this receptor influences the host–parasite battleground, and whether pharmacological blockade could reproduce the protective effect seen in knockout animals.

To answer these questions, the team led by Guangfeng Chen and Jiang Zhu infected mice experimentally with E. granulosus and then treated them for ninety days with either recombinant ghrelin protein or [D-Lys3]-GHRP-6, a well-characterized GHSR antagonist, delivered by intraperitoneal injection. The researchers then measured a battery of molecular and pathological indicators, including serum hormone levels, hepatic and lesion-perilesional gene and protein expression, proliferation markers, and fibrotic pathway activity. The long treatment window was designed to capture the chronic nature of hydatid disease, which unfolds over months rather than days in the natural host.

The results were strikingly bidirectional. In mice that received ghrelin, serum ghrelin concentrations rose and ghrelin/GHSR expression increased in both liver tissue and the tissue surrounding the parasitic lesions. These animals showed elevated levels of classic cell proliferation markers—Ki67, PCNA, Cyclin D1 and Cyclin E1—indicating heightened hepatocellular division. At the same time, ghrelin suppressed the hepatic TGF-β1/Smad3 fibrotic signaling pathway and reduced the abundance of fibrosis-associated proteins including alpha-smooth muscle actin, Collagen I and Collagen III. The net effect was deleterious for the host: ghrelin treatment promoted the progression of hepatic E. granulosus infection, effectively giving the parasite more room and resources to expand.

The antagonist told the opposite story. When infected mice were given [D-Lys3]-GHRP-6, serum ghrelin fell and hepatic ghrelin/GHSR levels declined. Expression of the cell proliferation-related proteins dropped, while the TGF-β1/Smad3 fibrotic pathway was activated and fibrotic protein expression increased. Pathologically, this shift translated into a denser fibrotic capsule forming around the parasite and a measurable alleviation of infection progression. In other words, shutting down the ghrelin signal encouraged the liver to wall off the parasite behind scar tissue rather than nurturing it with proliferating host cells.

The mechanistic logic of this finding reframes fibrosis in an unexpected light. In most liver diseases, fibrosis is the villain—a runaway wound-healing response that culminates in cirrhosis and organ failure. But in the context of a parasitic cyst, the fibrotic capsule is a defensive structure, a biological containment wall that restricts the parasite’s access to nutrients and space. By suppressing the TGF-β1/Smad3 axis, ghrelin appears to soften this wall and simultaneously drive the proliferation of host cells that the growing cyst can exploit. Blocking GHSR reverses both effects at once, tightening the enclosure and starving the lesion of proliferative support.

The study builds on a coherent line of earlier evidence. Research in rodents has shown that ghrelin can attenuate hepatocellular injury and liver fibrogenesis in toxic and cirrhotic models, and subsequent work linked ghrelin signaling to TGF-β1 regulation and autophagy in fibrotic livers. Within echinococcosis research specifically, the group had previously reported that ghrelin modulates immunoinflammation and fibrosis in infected liver lesions, and that GHSR gene knockout reduces parasite survival and alleviates the pathological liver response. The new pharmacological data close an important gap by demonstrating that a receptor antagonist—a class of molecules that can, in principle, be developed into drugs—achieves the same protective phenotype as genetic deletion.

Several caveats temper the enthusiasm. The experiments were conducted in mice over a defined ninety-day window, and cystic echinococcosis in humans develops over years within a more complex immune environment. [D-Lys3]-GHRP-6 is a research tool rather than a clinical compound, and chronic GHSR blockade would need to be weighed against ghrelin’s physiological roles in appetite, growth hormone secretion, cardiovascular function and energy homeostasis. Safety, dosing, delivery and efficacy in large animal models of hydatid disease all remain to be established before any translational pathway can be contemplated. The authors also note that the raw data underlying the study are available from the corresponding author upon reasonable request, and the work was approved by the institutional animal ethics committee.

Even so, the study adds a genuinely novel dimension to echinococcosis research by connecting neuroendocrine metabolism to parasite containment. If the mechanism holds in further models, GHSR antagonists—or upstream regulators of the ghrelin system such as the antagonist peptide LEAP-2—could inspire a new class of host-directed therapies for cystic echinococcosis, complementing or even replacing direct antiparasitic drugs that the parasite has limited susceptibility to. For a disease that the World Health Organization has listed among the neglected tropical diseases, and for which current pharmacotherapy falls short in many patients, the idea that a hunger hormone receptor could help the liver imprison its invader is the kind of counterintuitive insight from which new treatments are often born.

Subject of Research: Role of ghrelin receptor signaling in hepatic Echinococcus granulosus infection and liver fibrosis

Article Title: Ghrelin Receptor Blockade Restricts Hepatic Echinococcus granulosus Infection by Suppressing Host Cell Proliferation and Enhancing Fibrotic Encapsulation

Article References: Chen, G., Dilixiati, B., Zhou, T., Rao, X., Aimidoula, R., Zhang, W., Zhao, H., Wusiman, A., & Zhu, J. (2026). Ghrelin Receptor Blockade Restricts Hepatic Echinococcus granulosus Infection by Suppressing Host Cell Proliferation and Enhancing Fibrotic Encapsulation. Acta Parasitologica, 71(5), Article 225. https://doi.org/10.1007/s11686-026-01407-w

Image Credits: AI Generated

DOI: 10.1007/s11686-026-01407-w

Keywords: cystic echinococcosis, Echinococcus granulosus, ghrelin, GHSR, liver fibrosis, TGF-beta/Smad3, cell proliferation, parasitology, hydatid disease, G protein-coupled receptor, host-directed therapy, fibrotic encapsulation

The research, conducted by an Argentine team working with cell and molecular models of AML, focused on the glucocorticoid receptor, a nuclear receptor that, upon binding its ligand, translocates to the nucleus and modulates gene expression both directly, through binding to specific DNA sequences called glucocorticoid response elements, and indirectly, through interactions with other transcription factors. Glucocorticoids regulate nearly twenty percent of genome activity, and their transcriptional output is shaped by a web of cross-talking signaling pathways. The laboratory had previously shown that histamine signaling through the H1 receptor can modulate glucocorticoid receptor activity through a dual mechanism, potentiating the receptor via G-protein beta-gamma subunits while inhibiting it through the G-alpha-q pathway. The new work asked whether the H2 receptor, a related G-protein-coupled receptor, exerts similar control.

To answer this question, the researchers used the H2 receptor agonist amthamine alongside dexamethasone, a synthetic glucocorticoid, in engineered cell systems. When cells co-expressing the glucocorticoid receptor and the H2 receptor were treated with amthamine before dexamethasone, the maximal transcriptional response driven by the steroid increased by roughly fifty percent, measured with a luciferase reporter built from tandem glucocorticoid response elements. Notably, the potency of dexamethasone was essentially unchanged, indicating that amthamine amplified the ceiling of glucocorticoid-driven transcription rather than making the receptor more sensitive to its ligand. The effect was traced to signaling cascades downstream of the receptor rather than any direct interaction between histaminergic ligands and the glucocorticoid receptor itself, since inhibitors of those cascades abolished the potentiation.

Unpacking the mechanism revealed a strikingly composite picture. Activation of the H2 receptor canonically splits the G-alpha-s subunit from the G-protein beta-gamma dimer, raising intracellular cAMP. Paradoxically, this cAMP arm worked against the glucocorticoid receptor: directly stimulating adenylyl cyclase with forskolin reduced dexamethasone-induced receptor activity, and that inhibition was reversed by H89, a protein kinase A inhibitor, identifying PKA as the mediator of cAMP’s negative influence. The beta-gamma arm, by contrast, pushed in the opposite direction. Amthamine increased ERK phosphorylation while dampening PI3K-Akt and mTOR signaling, and blocking G-beta-gamma with the inhibitor gallein eliminated the potentiation. A MEK inhibitor completely abolished the amthamine effect, whereas inhibiting PI3K or mTOR on their own actually boosted glucocorticoid receptor activity, confirming that these pathways normally restrain the receptor. The net result of H2 receptor activation is therefore a contest between inhibitory cAMP signaling and stimulatory beta-gamma signaling, with the stimulatory side prevailing.

Intriguingly, the team found that clinically used H2 receptor inverse agonists, including cimetidine, famotidine and ranitidine, the familiar heartburn drugs, also enhanced dexamethasone-driven reporter activity. These ligands behave as ERK-biased antagonists, decreasing cAMP while increasing ERK phosphorylation, which tilts the same signaling balance toward potentiation. The finding raises the provocative possibility that widely available antihistamines could, in principle, modulate glucocorticoid signaling, although the authors stress that their study was conducted in cell models and that such a repurposing remains speculative.

The critical question was whether the artificial reporter results would hold for real genes in leukemic cells. In U937 cells, a human AML model, dexamethasone induced the expression of three endogenous glucocorticoid receptor target genes, GILZ, MKP1 and ANXA1, and amthamine co-treatment enhanced all three. But when the experiments were repeated in a U937 clone engineered to overexpress the H2 receptor, the picture became gene-specific: amthamine’s enhancement persisted for ANXA1, vanished for GILZ, and flipped to inhibition for MKP1. The researchers attribute this heterogeneity to differences in promoter architecture. GILZ is driven by tandem high-affinity glucocorticoid response elements, MKP1 by a single chromatin-remodeling element dependent on the coactivator p300, and ANXA1 by a tethering mechanism that does not require direct receptor binding to DNA. Each architecture confers different sensitivity to competition for limiting coactivators such as CBP/p300, and the relative stoichiometry of receptors, G-proteins and the glucocorticoid receptor itself determines the transcriptional outcome for each gene.

The functional consequences for leukemic cell behavior proved equally nuanced. Dexamethasone displayed a biphasic effect on U937 proliferation: low concentrations, from 0.1 to 10 nanomolar, actually increased cell growth, while higher concentrations suppressed it. Amthamine pretreatment dampened the pro-proliferative effect of low-dose dexamethasone without altering the antiproliferative action of high doses. Mechanistically, low-dose dexamethasone increased phosphorylation of S6K, a readout of mTOR pathway activity, and amthamine blocked this increase. Pharmacological mimicry supported the model: forskolin, the PI3K inhibitor wortmannin and rapamycin all hindered the proliferative effect of low-dose dexamethasone, and only rapamycin additionally boosted the antiproliferative effect of high doses. Consistent with these changes, low-dose dexamethasone reduced expression of the differentiation marker CD14, while high doses increased it, alongside parallel changes in the proliferation-related genes GADD45-beta and CDKN1A.

The most clinically resonant experiments involved cytarabine resistance. The team generated a U937-derived clone, U937-640R, that tolerates cytarabine concentrations more than two hundred times higher than the roughly 1.5 nanomolar IC50 that kills parental cells. In these resistant cells, dexamethasone alone re-sensitized the population to cytarabine, pulling the IC50 down from an effectively unmeasurable level to 3.7 nanomolar at a 10 nanomolar dexamethasone dose and to 20 nanomolar at 1 micromolar. Amthamine then produced a paradoxical, dose-dependent modulation: combined with low-dose dexamethasone, it shifted the cytarabine IC50 even lower, to 1.1 nanomolar, but with high-dose dexamethasone it pushed the IC50 back up to 170 nanomolar. In other words, the H2 agonist amplified chemosensitization at steroid doses low enough to minimize side effects but undermined it at high doses. In the sensitive parental cells, by contrast, neither drug alone nor in combination significantly shifted the cytarabine response curve, underscoring that the combination strategy is specifically relevant to the resistant state.

The authors propose a working model centered on REDD1, a canonical glucocorticoid receptor target gene that represses mTOR. In their framework, low glucocorticoid receptor occupancy fails to induce enough REDD1 to counter a constitutive mTOR-activating pathway, so cells proliferate; at higher occupancy, REDD1 induction overrides that pathway and proliferation halts. H2 receptor signaling may intervene at two points, both by lowering mTOR activity independently of the glucocorticoid receptor and by potentiating receptor activity enough to lower the occupancy threshold for REDD1 induction, thereby converting AML’s biphasic glucocorticoid response into a monotonically antiproliferative one. The model also connects to a broader re-evaluation of glucocorticoid resistance in AML: dexamethasone added to intensive chemotherapy has been associated with reduced relapse and improved survival in hyperleukocytic AML, an effect enriched in NPM1-mutated disease, and the recent DEXAML-02 Phase II trial has provided a first prospective clinical signal in older patients. Histamine itself already holds an approved niche in the disease, since histamine dihydrochloride combined with interleukin-2 has been used as maintenance therapy to prevent AML relapse by protecting antitumor lymphocytes and natural killer cells from oxidative damage.

The study’s practical implication is that pairing an H2 receptor agonist with low-dose dexamethasone could allow lower glucocorticoid and chemotherapy exposures while maintaining or enhancing antileukemic efficacy, a strategy that would matter greatly given the substantial adverse effects of chronic steroid use. The authors are careful to note the limitations: all results derive from a single cell line, and validation across additional models and primary AML samples is essential before any clinical translation. Even so, the demonstration that a histamine receptor can rewire glucocorticoid receptor transcription in a gene- and context-dependent manner, and that this rewiring can resensitize chemoresistant leukemic cells at low steroid doses, adds a compelling new dimension to the pharmacology of an old drug class and offers a fresh lead in the search for less toxic AML combinations.

Subject of Research: Cross-talk between the histamine H2 receptor and the glucocorticoid receptor in acute myeloid leukemia treatment

Article Title: Cross‐Talk Between Histamine H2 Receptor and Glucocorticoid Receptor: Potential Implications in Acute Myeloid Leukemia Treatment

Article References: Torralba‐Agu, V., Fernández, N., Shayo, C., Davio, C., Zappia, C. D., & Monczor, F. (2026). Cross‐Talk Between Histamine H 2 Receptor and Glucocorticoid Receptor: Potential Implications in Acute Myeloid Leukemia Treatment. Pharmacology Research & Perspectives, 14(5), Article e70314. https://doi.org/10.1002/prp2.70314

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DOI: 10.1002/prp2.70314

Keywords: acute myeloid leukemia, glucocorticoid receptor, histamine H2 receptor, dexamethasone, cytarabine resistance, amthamine, mTOR signaling, G-protein-coupled receptor, REDD1, chemosensitization, U937 cells, leukemia therapy

GPR84 belongs to a subgroup of GPCRs that respond to medium-chain fatty acids, the metabolic fragments released when fats are broken down. Because these fragments accumulate in tissues under metabolic stress, GPR84 is thought to act as a metabolic sensor for the immune system, translating changing lipid levels into altered cellular behavior. Decades of pharmacological studies have linked the receptor to macrophages, neutrophils and other innate immune cells, where its activation has been associated with amplified production of inflammatory signaling molecules. That association made GPR84 an attractive drug target for companies pursuing anti-inflammatory therapies, and it also made the receptor a cautionary tale: several clinical candidates targeting it were halted, in some cases because the biology proved more complicated than early animal studies suggested.

The central problem has been that GPCRs are not simple on-off switches. They are dynamic molecular machines that sample a range of conformations, and different ligands can stabilize different subsets of those conformations. A ligand that locks the receptor into a fully active shape will recruit signaling proteins robustly, while a ligand that favors inactive shapes will silence the pathway. But many ligands do something subtler: they stabilize partially active conformations, or they favor active shapes in one signaling branch while leaving others untouched. Without structural information, medicinal chemists were essentially adjusting molecular shapes blindly, hoping that small changes in a ligand scaffold would produce predictable changes in receptor behavior.

The new study addresses that gap by capturing GPR84 in two distinct functional states, allowing the researchers to compare the receptor’s architecture when it is being activated against its architecture when it is being blocked or modulated. Structures determined in multiple states are technically demanding, because a membrane-embedded receptor must be stabilized in each conformation long enough to be imaged at atomic resolution. Achieving this typically requires engineered variants, stabilizing antibodies or nanobodies, and carefully chosen ligands that preferentially hold the receptor in the desired state. The resulting paired structures function like two frames of a molecular movie, revealing which helices shift, which side chains rotate, and which structural water molecules rearrange as the receptor transitions between resting and signaling-competent forms.

Comparing the two states highlights the allosteric heart of the receptor. In GPCRs, ligand binding at a pocket nestled among the transmembrane helices is transmitted through a conserved relay of hydrogen bonds, salt bridges and hydrophobic contacts to the intracellular face, where G proteins and other effectors dock. The dual-state GPR84 structures delineate how agonist binding contracts this relay into the canonical active arrangement, with an inward movement of the extracellular portion of a key transmembrane helix and a corresponding outward swing on the intracellular side that opens the effector-binding cavity. In the inactive or antagonist-bound state, that same helix relaxes outward, the intracellular cavity collapses, and the network of polar interactions reconfigures into a pattern incompatible with effector coupling. The residue-by-residue map of these changes gives chemists concrete positions to target when they want to bias the equilibrium toward one state or the other.

Crucially, the structural work is not left to stand alone. The authors couple it with functional assays performed in immune cells, measuring how well each ligand drives or suppresses downstream signaling and, importantly, how it affects inflammatory outputs such as cytokine release. This combination is what elevates the study from structural description to pharmacological instruction. A structure can suggest that a compound should be an agonist, but only cellular assays reveal the potency, the efficacy ceiling, and whether the compound behaves as a full agonist, a partial agonist or a biased ligand in a physiologically relevant context. By testing ligands across the spectrum, the researchers could correlate specific structural features of the binding pocket with specific functional consequences, effectively building a translation table between atomic geometry and immune cell behavior.

One of the more interesting implications concerns ligand bias, the phenomenon in which a receptor signals preferentially through one intracellular pathway over another. For GPR84, whose activation intersects with inflammatory programs in macrophages, a biased ligand could in principle dampen harmful signaling while preserving useful functions, or vice versa. The dual-state structures provide a mechanistic handle on bias: ligands that engage only part of the activation relay, or that fail to complete certain helical movements, may recruit one effector but not another. The immune functional assays then quantify what that partial engagement means for cytokine production, giving drug developers a rational framework for designing compounds with tailored signaling profiles rather than accepting whatever profile a scaffold happens to produce.

The study also speaks to the thorny issue of species differences, which has plagued GPR84 drug development. Synthetic agonists developed against the human receptor have often shown sharply different potency in mouse models, complicating the interpretation of preclinical efficacy studies and contributing to the sector’s clinical disappointments. Although the structures presented are of the human receptor, the detailed pocket architecture allows researchers to pinpoint which residues differ across species and to predict, before expensive animal work, whether a given compound is likely to translate. That kind of structural triage could save years of effort and redirect resources toward candidate molecules with a realistic chance of reproducing human biology in animal systems.

Beyond immediate drug design, the work contributes to a broader shift in GPCR pharmacology toward state-based thinking. Rather than classifying ligands simply as agonists, antagonists or inverse agonists, the field increasingly describes them by the conformational ensembles they stabilize and the signaling outputs those ensembles produce. GPR84, with its metabolic ligands, its immune cell expression and its checkered clinical history, is an ideal test case for this framework. The demonstration that paired structures plus immune assays can jointly explain and predict pharmacological behavior provides a template that other lipid-sensing and metabolite-sensing receptors could follow, particularly those where immune modulation is the therapeutic goal.

For patients, the significance lies in what this molecular clarity could eventually enable. Chronic inflammatory and metabolic diseases, including conditions involving macrophage-driven tissue damage, remain areas of substantial unmet need, and receptors that sense the metabolic environment of inflamed tissue are logical points of intervention. By showing exactly how ligands of different pharmacological classes occupy the GPR84 binding pocket and drive or block its conformational changes, the study turns a previously opaque target into an addressable one. The next steps, testing structure-guided ligand designs and validating their immune effects in disease models, will determine how quickly this structural knowledge moves from the pages of a journal toward the clinic, but the roadmap for modulating GPR84 rationally is now drawn.

Subject of Research: Structural and pharmacological modulation of the lipid-sensing immune receptor GPR84

Article Title: Pharmacological modulation of GPR84 revealed by dual states structures and immune functional assays

Article References: Choi, M. K., Park, D. J., Kim, P., Choi, H. S., Myung, S., Yoo, Y., Chang, N., Yoon, G.-Y., Kang, H. J., Ha, S.-J., & Cho, H.-S. (2026). Pharmacological modulation of GPR84 revealed by dual states structures and immune functional assays. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01841-w

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01841-w

Keywords: GPR84, G protein-coupled receptor, dual-state structures, immune functional assays, ligand bias, inflammatory signaling, macrophages, medium-chain fatty acids, structural biology, drug discovery, Pharmacological, modulation