Ewa Krawczyk

Finerenone, a nonsteroidal mineralocorticoid receptor (MR) antagonist, has shown promise in protecting against kidney damage in obese, insulin-resistant mice. It effectively prevents albuminuria, inflammation, fibrosis, and mitochondrial dysfunction, while also restoring estrogen-related receptor-γ (ERRγ) expression. These results suggest that finerenone could play a key role in halting the progression of kidney disease by enhancing mitochondrial function and reducing harmful lipid accumulation, offering a potential therapeutic strategy for managing kidney complications in metabolic disorders.

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD) and remains a significant clinical challenge due to its complex pathogenesis. This review explores the intricate interplay of metabolic, inflammatory, and cellular mechanisms that drive DKD progression, with a particular focus on lipid metabolism, mitochondrial dysfunction, oxidative stress, inflammation, cell injury, and epigenetic modifications. Advances in histopathological and molecular studies have expanded our understanding of glomerular, tubular, and vascular abnormalities in DKD, highlighting the critical role of nuclear hormone receptors, transcription factors, and G protein-coupled receptors in regulating renal lipid accumulation, mitochondrial function, inflammation, oxidative stress, and fibrotic pathways. In addition, emerging evidence implicates novel cell death mechanisms, including ferroptosis, necroptosis, pyroptosis, and PANoptosis, in DKD pathology. Epigenetic modifications, including DNA methylation, histone modifications, and noncoding RNAs, further contribute to disease progression by regulating gene expression in response to metabolic stress. As current therapeutic strategies remain insufficient to prevent DKD progression, this review also discusses novel molecular targets and emerging therapeutic approaches aimed at mitigating lipid toxicity, enhancing mitochondrial function, and suppressing inflammation. By integrating insights from histopathology, molecular biology, and translational research, this review provides a comprehensive framework for developing future strategies to delay or prevent DKD progression.

Correction on: Krawczyk E, Cavalli LR and Kitlinska J (2025) Editorial: Current status and recent advances in preclinical models for rare cancers. Front. Oncol. 15:1676020. doi: 10.3389/fonc.2025.1676020 In the published article, there were mistakes in the Author affiliation statements. The affiliation for Dr. Luciane R Cavalli was displayed as: "2 Instituto de Pesquisa Pele Pequeno Principe, Curitiba, Brazil". The correct statement is: "2 Instituto de Pesquisa Pele Pequeno Principe, Curitiba, Brazil. 3 Department of Oncology, Georgetown University Medical Center, Washington, DC, United States". The affiliation for Dr. Joanna Kitlinska was displayed as: "1 Department of Pathology, Georgetown University Medical Center, Washington, DC, United States". The correct statement is: "4 Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC, United States".

Despite their disadvantages, preclinical models in vitro are still crucial for every area of biomedical science. They remain a necessary basis for biological, biochemical, and mechanistic studies of pathophysiology of human disease, evaluation of diagnostic tests, assessment of vaccines, as well as screening of potential and repurposed drugs before they are adapted to clinical use. In contrast to animal models in vivo, preclinical in vitro models are cost and time effective. They are easier to use, and, in most cases, they are not associated with ethical concerns. Therefore, they are extensively used in cancer research. Conditional cell reprogramming (CCR) has been one of the novel technologies utilized as a preclinical model in vitro for various common cancers and other diseases. It may be even more important for the research related to rare cancers—elusive, difficult to study, and with insufficient number of relevant models available. Applications of this technology for the basic and translational studies of rare cancers are described in this article. Evaluation of the mechanisms of tumorigenicity and metastasis in neuroblastoma, neuroendocrine cervical carcinoma, ependymoma and astrocytoma, as well as screening of potential drugs and other therapeutic approaches for the laryngeal and hypopharyngeal carcinoma and adenoid cystic carcinoma, demonstrate that the CCR technology is a potential reliable model for various aspects of rare cancer research in the future.

Editorial: Current Status and Recent Advances in Preclinical Models for Rare Cancers Ewa Krawczyk, Luciane Cavalli, Joanna Kitlinska Despite advancements in diagnostic and successful therapies, cancer still poses an important threat to human health. Global burden of oncological diseases is significant -according to WHO, recently above 20 million new cases are diagnosed and more than 9 million people die per year because of various malignancies. Moreover, due to multiple factors, including aging of the societies, the number of cancer cases is predicted to increase in the near future. Therefore, all initiatives aimed at designing new diagnostic methods or novel therapeutic approaches are valuable and critically needed.Preclinical assays, both in vitro and in vivo, remain a crucial part of cancer research. They are indispensable in every aspect of basic and translational medicine, from drug screening and repurposing, vaccine development, to researching the mechanisms of the disease. However, no preclinical model is perfect, and none of them recapitulates exactly the physiology and pathophysiology of a human organism.For example, cell culture models in vitro lack the complexity of heterogenic cancer structure and cellular composition, so using them to test interactions of cancer cells with microenvironment and immune system is challenging. As an alternative, three-dimensional preclinical models can be utilized for that purpose, although they are limited by a high cost and low-throughput. Conversely, animal models in vivo retain more relevance to humans, but they are not time and cost efficient, and ethical issues have been raised against them.Nevertheless, preclinical disease models are important for cancer research, and there is an urgent need for the advancement in this area and development of new reliable methods. These new methods and techniques can facilitate research for commonly occurring cancers, but they are probably even more important for rare malignancies. Rare cancers research, due to their infrequent occurrence, limited availability of human tissues and scarce preclinical models, is especially challenging and can be often neglected. Therefore, an advancement in this area is essential. This edition of Research Topic is a collection of research and review articles demonstrating the importance of various types of preclinical models in rare cancers research. Three of them focus on sarcomas, emphasizing the difficulties in diagnosis and insufficient treatment options for these diseases. Altogether, excellent research and review articles collected in this Research topic clearly demonstrate the current status as well as exciting advancements in rare cancers modeling, that may greatly facilitate and accelerate the development of new diagnostic and therapeutic approaches for these challenging malignancies.

Ewing sarcoma (ES) is a pediatric malignancy that lacks adequate therapies for its metastatic form. These tumors constitutively express neuropeptide Y (NPY) and its Y5 receptor (Y5R), which leads to elevated levels of the peptide in patients' serum. In animal models, xenografts secreting NPY metastasize to extrapulmonary niches, including bone; the phenotype associated with adverse prognosis in ES patients. To determine the role of the NPY/Y5R axis in ES extrapulmonary dissemination, we used a doxycycline-inducible CRISPR/Cas9 system to knockout Y5R in SK-ES-1 xenografts that metastasize to these niches. We have shown that metastases developing from heterogenous SK-ES-1/Y5R-sgRNA primary tumors in doxycycline-treated mice were initiated exclusively by SK-ES-1 clones with a functional NPY5R gene. Similarly, metastasis from wild type SK-ES-1 xenografts was associated with a selection of clones with NPY5R gene gain. In vitro assays identified Y5R-dependent ES cell motility driven by RhoA activation as the mechanism underlying the metastatic effects of NPY. In ES cell lines that secrete NPY, the autocrine NPY/Y5R loop was responsible for maintaining basal cell motility, while ES cells that do not release the peptide responded to the exogenous NPY. These data provide evidence for the crucial role of the NPY/Y5R axis in ES metastasis.

Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Current studies determined the mechanisms of the beneficial kidney effects of the non-steroidal MR antagonist Finerenone (FN) in a mouse model of western diet-induced obesity and insulin resistance. 10-week-old male C57BL/6J mice were fed a low fat (LF) or a western diet (WD) for 12 weeks followed by treatment with either vehicle or finerenone (FN) for another 14 weeks (intervention studies) until they were 36 weeks old. Finerenone treatment prevented a) the increased albuminuria and kidney injury molecule 1 (KIM1), b) the expanded extracellular mesangial matrix, and podocyte injury, c) fibronectin, collagen IV, CD45 and CD68 immunostaining, d) glomerular basement membrane disruption, podocyte foot process loss, and mitochondrial structural abnormalities, e) the pro-inflammatory cytokines (MCP1), innate immunity pathways (TLR2, STING, STAT3), and fibrosis markers fibronectin, TGFβ and Pai1, and f) the increased kidney cholesterol levels. There was also reduced expression of nuclear receptor ERRγ without changes in ERRα in WD-fed mice whereas both ERRα and ERRγ expression levels increased after Finerenone treatment. NADH lifetime analysis showed decreased bound NADH, compatible with decreased mitochondrial OXPHOS in the kidneys of WD-fed mice compared to controls, which was prevented by finerenone treatment. In conclusion, Finerenone treatment exhibits a renal protective role and prevents the progression of kidney disease by regulating mitochondrial function, most likely via ERRγ, and reducing lipid accumulation and inflammation.

Neuropeptide Y (NPY) is a sympathetic neurotransmitter widely distributed in the peripheral and central nervous system, affecting many physiological functions. Consequently, dysregulation of the NPY system contributes to numerous pathological disorders, including stress, obesity, and cancer. The pleiotropic functions of NPY in humans are mediated by G protein-coupled receptors (Y1R, Y2R, Y5R), which activate several signaling pathways and thereby regulate cell growth, differentiation, apoptosis, proliferation, angiogenesis, and metabolism. These activities of NPY are highly relevant to tumor biology and known hallmarks of cancer, including sustained proliferative potential, resisting cell death, angiogenesis, invasion, and metastases. In this comprehensive review, we describe the cellular functions of NPY and discuss its role in cancer pathobiology, as well as provide the current state of knowledge pertaining to NPY and its receptors in various cancer types. Moreover, we focus on potential clinical applications targeting the NPY system, such as its role as a prognostic and predictive factor, as well as its utility in cancer diagnostics, imaging, and treatment. Altogether, growing evidence supports the significant role of the NPY system in tumor pathobiology and implicates its potential therapeutic and diagnostic value in modern oncology.