Editorial: Zebrafish: Bona Fide Pathophysiological Models of Human Diseases

Nicola Facchinello^1,2*Antionette Latrece Williams^3,4*Natascia Tiso^5*

• ¹Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
• ²Neuroscience Institute, Italian Research Council (CNR), Padova, Italy
• ³Division of Ophthalmology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, United States
• ⁴Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, United States
• ⁵Department of Biology, University of Padua, Padua, Italy

Guzelkaya et al. present a zebrafish model of neonatal hyperbilirubinemia to investigate bilirubininduced neurological dysfunction (BIND), a condition still poorly understood in human neonates. Their study shows that bilirubin exposure impairs zebrafish locomotion and brain morphology, providing a vertebrate platform for dissecting bilirubin toxicity and testing neuroprotective interventions [1]. In a related exploration of nervous system pathology, Nies et al. employ a rotenone-induced Parkinson's disease model in zebrafish to assess the therapeutic potential of human metallothionein II (hMT2). Their findings reveal that hMT2 not only mitigates dopaminergic neurodegeneration and oxidative stress but also restores locomotor function, highlighting zebrafish as a translational platform for screening neuroprotective compounds [2]. The vertebrate cardiac system is another focal point addressed in this collection. Angom et al. use a forward genetic screen with gene-breaking trap lines to uncover grin2bbART, a novel long noncoding RNA that regulates calcium handling in the zebrafish heart. This study underscores the capacity of zebrafish as a model for uncovering regulators of heart physiology that might otherwise remain elusive in mammalian systems [3]. In a related study, Apolínová et al. present ZebraReg, an innovative automated platform that leverages the innate ability of zebrafish to regenerate heart tissue after injury. This tool allows for high-throughput screening of genes and compounds that influence cardiac regeneration, with clear translational implications for regenerative medicine in humans [4]. In the domain of metabolic disease, Zeng et al. investigate cobll1a, a gene encoding a putative cytoskeletal protein involved in lipid metabolism. Their work shows that cobll1a-deficient zebrafish exhibit hepatic lipid accumulation due to disrupted retinoic acid signaling, linking this pathway to metabolic disorders, such as fatty liver disease and obesity. These findings reinforce the relevance of zebrafish for modeling and delineating the pathophysiological origins of complex metabolic syndromes [5]. Zebrafish also continue to provide crucial insights into developmental genetics and organogenesis. Ercanbrack et al. study the effects of frataxin knockdown in zebrafish embryos, modeling Friedreich's Ataxia-a neurodegenerative disorder with mitochondrial dysfunction. These authors report defects in pronephros (early kidney) formation and embryonic development, expanding our understanding of the systemic roles of frataxin and its links to renal phenotypes in human disease [6]. Zebrafish are immensely useful and popular genetic models for studying craniofacial development.In the present collection, Fox and Waskiewicz review the contributions of zebrafish to understanding the roles of TGF-β and BMP signaling pathways in craniofacial morphogenesis. These authors highlight how zebrafish models replicate key features of congenital anomalies, such as cleft palate and craniosynostosis, offering a tractable system to study gene-environment interactions that influence facial structure [7]. Finally, Rossen et al. offer a comprehensive review of how zebrafish are used to model congenital cataracts, particularly those involving crystallin gene mutations. Given the high degree of conservation in lens development between zebrafish and humans, these models allow for real-time imaging of lens transparency and the testing of gene variants implicated in pediatric vision loss. This study highlights the zebrafish as a valuable model for both basic ocular research and therapeutic screening [8]. Together, these contributions exemplify the breadth and depth of zebrafish disease modeling. Across these studies, a variety of methodological approaches are employed, including CRISPR-based gene editing, morpholino knockdowns, transgenic reporters, forward genetic screens, and high-throughput imaging and behavioral assays. These tools enable fine-scale dissection of cellular and molecular processes in vivo and at scale-an asset particularly valuable for preclinical discovery pipelines. Importantly, several studies in this collection employ advancements beyond modeling toward therapeutic exploration. Nies et al. demonstrate the efficacy of hMT2 in ameliorating Parkinsonian phenotypes [2], while ZebraReg offers a pipeline for regenerative compound discovery [4]. Such efforts underscore the translational potential of zebrafish not just as disease models but also as platforms for therapeutic innovation. This collection of studies also reflects the ability of zebrafish modeling to integrate systems-level insights. For example, links between developmental signaling and metabolic disease [5], or mitochondrial dysfunction and renal development [6], illustrate the capacity of zebrafish models to reveal inter-organ and cross-pathway relationships that mirror human physiology and pathology. Altogether, these studies affirm the zebrafish as a bona fide model of human disease, revealing the application of these animals in elucidating disease mechanisms, uncovering new gene functions, and screening therapeutics for a multitude of diseases ranging from monogenic conditions to complex multifactorial disorders. As research advances toward more patient-specific and systems-based approaches, zebrafish remain a cornerstone of translational research, bridging molecular discoveries to practical applications for the prevention of diseases and improvement of human health outcomes.