The research team, led by Shuo Yang, Yongjing Li, Deqi Sun, Chenyu Shi, Qi Li and Shikai Liu of the Ocean University of China in Qingdao, tackled a question that has long frustrated biologists working on indirectly developing animals. Many marine invertebrates pass through a larval stage that looks and behaves nothing like the adult, and metamorphosis demands that the nervous system be substantially reworked to serve a completely different lifestyle. In the Pacific oyster, Magallana gigas, the larva swims and senses its surroundings using structures such as the apical organ, but once it cements itself to a surface, those larval systems are largely discarded and adult ganglia take over. How the adult nervous system is organized, and whether its different ganglia have specialized roles, had remained unresolved at the cellular level.

Single-nucleus RNA sequencing offered a way in. Rather than profiling whole tissues, which averages signals across many cell types, the technique captures the transcriptome of individual nuclei, allowing researchers to identify and classify every major cell type present. The team applied this approach to the adult cerebral ganglia, known as CG, and the visceral ganglion, or VG, generating cell-type atlases that distinguish neurons, glial cells and other supporting populations. Comparative analysis of the two atlases revealed clear ganglion-associated differences in cellular composition and in the transcriptional programs running inside the neurons themselves, suggesting that the two structures do genuinely different jobs for the animal.

Those differences showed up most clearly in pathway-level analyses. Using differential expression testing, enrichment of KEGG pathway annotations, and a single-cell method called AUCell that estimates gene set activity in each individual cell, the researchers found that neurons of the cerebral ganglia were transcriptionally biased toward homeostatic and protective processes. In practical terms, the CG neurons expressed gene programs associated with maintaining internal stability and defending the animal against stress. The visceral ganglion told a different story. Its neurons showed higher activity in pathways linked to signal modulation and effector output, consistent with a role in regulating the muscular and physiological actions of an animal that must pump water, filter food and manage its internal organs while anchored in place.

Importantly, these functional biases were not simply a by-product of having different mixtures of cell types in the two ganglia. The team compared transcriptionally matched neuronal populations, meaning neuron groups in the CG and VG that are molecularly similar to one another, and found that the pathway differences persisted even then. The biases were also accompanied by distinct patterns of transcription factor expression, the master regulatory genes that shape a cell’s identity and behavior. This indicates that the two ganglia are governed by different regulatory logic at a fundamental level, not just different sums of their parts.

One of the study’s most striking findings concerned serotonin, the neurotransmitter better known by its chemical name 5-hydroxytryptamine, or 5-HT. Serotonergic neurons, those that produce and use serotonin as their signaling molecule, were primarily identified in the visceral ganglion. No corresponding population could be resolved in the cerebral ganglia. To understand how this serotonergic program is controlled, the researchers deployed a suite of computational tools. Virtual knockout experiments, which simulate the loss of specific regulatory genes, together with gene regulatory network inference using the GENIE3 algorithm and pseudotime analysis, which orders cells along a developmental trajectory, converged on a candidate Gata3–Pitx–Uncx regulatory module associated with the 5-HT program. In other words, three families of transcription factors appear to work in concert to define and maintain the oyster’s serotonergic neurons.

The atlases also illuminated the often-overlooked supporting cast of the nervous system. Among the non-neuronal cells, the team identified a population they describe as metabolic glial cells, which displayed gene expression features related to transport, redox balance, detoxification and amino acid metabolism. To test whether these cells truly resemble glia, the researchers combined cell–cell communication analysis, pseudotime modeling, and a cross-species cell-type similarity approach called SAMap, which aligns single-cell datasets from different organisms. All three lines of evidence supported a glial-like identity for these cells and suggested that they may perform neural-support functions analogous to those of glial cells in better-studied animals, providing metabolic and protective services to the surrounding neurons.

Placed alongside earlier work on the larval apical organ, the new findings allow the authors to propose a working model of neural adaptation across the oyster’s life cycle. In the larva, the apical organ serves as the dominant sensory and integrative hub. After metamorphosis, the model suggests, functional emphasis may shift toward the adult visceral ganglion, which takes on responsibilities suited to the sessile adult, from coordinating effector outputs to housing the serotonergic signaling system. The cerebral ganglia, meanwhile, lean toward homeostatic upkeep. This is framed as a testable framework rather than a settled conclusion, and the authors point the way toward future experimental validation, for example by functionally perturbing the candidate regulatory module or the serotonergic neurons to see how oyster behavior and physiology respond.

Beyond molluscan biology, the study has broader resonance. Single-cell and single-nucleus atlases have transformed vertebrate neuroscience, but invertebrate nervous systems, particularly those of animals that undergo radical metamorphosis, remain largely unmapped. The oyster, as an economically critical aquaculture species and an ecologically important reef builder, offers a system in which neural adaptation can be studied against a well-defined life-history transition. Understanding how its ganglia specialize could inform breeding and hatchery practices, since larval settlement and post-metamorphic survival are major bottlenecks in oyster aquaculture, and both depend on a nervous system that has successfully navigated its remodeling.

The work also adds to a growing appreciation that nervous system evolution and development operate with remarkable flexibility. A regulatory module involving Gata3, Pitx and Uncx family factors steering a serotonin program, and glial-like cells devoted to metabolism and detoxification, suggest that the molecular grammar of neural support and modulation is deeply conserved, even as the anatomical solutions differ wildly between a bivalve and a mammal. For now, the adult oyster’s brain, long treated as a diffuse and undifferentiated tangle, has revealed itself to be a compartmentalized, molecularly specialized organ, and its secrets are only beginning to come into focus.

Subject of Research: Single-nucleus transcriptomics of adult Pacific oyster cerebral and visceral ganglia to characterize neural remodeling after metamorphosis.

Article Title: Single-nucleus transcriptomics reveals cellular signatures of adaptive remodeling in the adult oyster nervous system after the life-history transition

Article References: Yang, S., Li, Y., Sun, D., Shi, C., Li, Q., & Liu, S. (2026). Single-nucleus transcriptomics reveals cellular signatures of adaptive remodeling in the adult oyster nervous system after the life-history transition. BMC Biology. https://doi.org/10.1186/s12915-026-02743-z

Image Credits: AI Generated

DOI: 10.1186/s12915-026-02743-z

Keywords: Pacific oyster, Magallana gigas, single-nucleus RNA sequencing, metamorphosis, serotonergic neurons, visceral ganglion, cerebral ganglia, transcription factors, glial cells, neural adaptation, BMC Biology, gene regulatory network

Liver fibrosis arises when chronic injury from viral hepatitis, alcohol, fatty liver disease, or other insults pushes hepatic stellate cells into an activated, myofibroblast-like state. In their quiescent form, these cells store vitamin A and quietly regulate blood flow through the liver’s sinusoids. When activated, they proliferate, migrate, and deposit extracellular matrix faster than it can be degraded, gradually choking the organ’s architecture into the stiff, nodular tissue of cirrhosis. Despite decades of research, no approved therapy reverses established fibrosis; treatment has largely meant removing the underlying cause and hoping the liver’s own regenerative capacity keeps pace. Praziquantel had already shown hints of anti-fibrotic activity in experimental settings, but how a drug best known for paralyzing schistosome worms could calm scar-forming liver cells remained a mystery.

To crack that mystery, the research team, led by Zhongkui Lu and Guoying Zhang of Nanjing Integrated Traditional Chinese and Western Medicine Hospital affiliated with Nanjing University of Chinese Medicine, together with colleagues at Xuzhou Medical University and Jinling Hospital, assembled potential praziquantel targets from public pharmacological databases and cross-referenced them against genes implicated in liver fibrosis. The overlap yielded 137 candidate genes. Enrichment analyses of this set pointed toward pathways involving xenobiotic metabolism and neuroactive ligand-receptor interactions, a signature consistent with the drug’s known pharmacology but also hinting at receptor-mediated effects beyond simple parasite membrane disruption.

The next step was to find the critical nodes within this network. Using the STRING database to construct a protein-protein interaction map and Cytoscape to visualize and prune it, the researchers identified six hub genes at the center of the praziquantel-fibrosis intersection: EGFR, ALB, TP53, PTGS2, ESR1, and CYP3A4. These genes span a striking range of functions, from growth factor signaling and tumor suppression to drug metabolism and hormone reception. But which of them actually matters causally for fibrosis, rather than merely being correlated with it? To answer that question, the team turned to Mendelian randomization, a statistical technique that uses naturally occurring genetic variants as instruments to test whether an exposure, here the expression or function of a candidate gene, has a causal effect on an outcome.

The Mendelian randomization analysis delivered a clear verdict for one gene. ESR1, the estrogen receptor alpha gene, showed genetically supported evidence of a protective causal role against liver fibrosis. A colocalization analysis, which tests whether the same genetic variant drives both the gene signal and the disease association in a genomic region, nominated a specific variant, rs3020404, as a plausible functional basis for the link. In other words, the population genetics did not merely suggest that ESR1 expression tracks with fibrosis severity; it suggested that inherited differences in ESR1 activity genuinely shift fibrosis risk, making the receptor a credible therapeutic target rather than a bystander.

Genetic plausibility still needed a physical mechanism, and for that the researchers turned to molecular modeling. Molecular docking placed praziquantel within ESR1’s ligand-binding pocket, and molecular dynamics simulations confirmed that the drug-receptor complex remains stable over simulated time, with the small molecule maintaining consistent contacts with the receptor. The modeling cannot prove binding in a living cell on its own, but it established that praziquantel and ESR1 are chemically compatible partners, setting the stage for functional tests.

The most revealing layer of the study came from single-cell RNA sequencing of liver tissue. Analyzing the data with the Seurat framework, the researchers mapped ESR1 expression across the liver’s cellular ecosystem and found it broadly present, but with a telling pattern: quiescent hepatic stellate cells and a cytokine-producing stellate cell subset, dubbed cyHSCs, expressed significantly higher levels of ESR1 than activated myofibroblastic stellate cells, or myHSCs. The receptor that praziquantel appears to target is most abundant precisely in the cell states that fibrosis threatens to destroy or corrupt, suggesting the drug may act by reinforcing the quiescent, non-fibrogenic identity of these cells.

To probe what ESR1 actually does inside stellate cells, the team ran virtual knockout experiments using scTenifoldKnk, a computational method that predicts how silencing a gene rewires a single-cell gene regulatory network. Removing ESR1 in silico disrupted a network whose most prominent casualties included RXFP1, EGFLAM, and several mitochondrial genome components such as MT-CO1, MT-CO2, and MT-ND4L. Pathway analysis of the perturbed genes showed strong enrichment in oxidative phosphorylation and immune signaling, including T cell receptor signaling. The picture that emerges is of ESR1 as an orchestrator of mitochondrial metabolic homeostasis and immunoregulatory signaling in stellate cells; when it is lost, the cells’ energy metabolism falters and inflammatory programs gain ground, conditions that favor fibrogenic activation.

Computational predictions, however convincing, demand wet-lab confirmation, and the researchers provided it. Working with LX-2 cells, a widely used human hepatic stellate cell line, they silenced ESR1 and tested whether praziquantel could still exert its anti-fibrotic effects. It could not, at least not fully. The loss-of-function experiments confirmed that ESR1 is functionally required for the drug’s benefit, closing the loop between network prediction, genetic causality, structural modeling, and cellular mechanism. The authors propose that praziquantel activates ESR1, which in turn maintains a protective gene network preserving mitochondrial function and immune balance in stellate cells, thereby blocking their transition into collagen-secreting myofibroblasts.

The implications extend well beyond one drug and one receptor. Repurposing praziquantel, whose safety profile is established through mass administration programs across the tropics, could dramatically shorten the path to clinical testing for an anti-fibrotic indication compared with developing a novel molecule from scratch. More broadly, the study showcases an integrative strategy, combining network pharmacology, Mendelian randomization, colocalization, molecular dynamics, single-cell transcriptomics, virtual knockout, and in vitro validation, that can elevate a computational hypothesis to a mechanistically grounded candidate therapy. ESR1 modulation itself may prove a fruitful therapeutic direction independent of praziquantel, and the identification of rs3020404 as a candidate functional variant offers a genetic handle for stratifying patients most likely to benefit. Much work remains: the findings rest heavily on human cell lines and public datasets, and animal models and clinical trials will be needed to confirm that the mechanism operates in scarred livers in living patients. But the study reframes a familiar antiparasitic as a plausible antifibrotic and hands hepatology a genetically validated, druggable target at the heart of the stellate cell’s decision to scar or stay quiet.

Subject of Research: Network pharmacology and experimental validation identifying ESR1 as the target through which praziquantel alleviates liver fibrosis

Article Title: Praziquantel targeting ESR1 to alleviate liver fibrosis: a comprehensive network analysis insight

Article References: Lu, Z., Kong, D., He, F., Lv, H., Guo, Y., Xia, X., & Zhang, G. (2026). Praziquantel targeting ESR1 to alleviate liver fibrosis: a comprehensive network analysis insight. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08941-1

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08941-1

Keywords: praziquantel, liver fibrosis, ESR1, hepatic stellate cells, Mendelian randomization, molecular docking, single-cell RNA sequencing, drug repurposing, mitochondrial function, hepatology, gene regulatory network, LX-2 cells