ABSTRACT Fatty acid synthase (FASN) is the key catalytic enzyme of de novo lipogenesis and is increasingly recognized as a driver of metabolic reprogramming in genitourinary disease. In both malignant and non‐malignant settings, aberrant FASN expression and activity are associated with tumor growth, metastatic spread, drug resistance, renal lipotoxicity, fibrosis, and immune remodeling. However, current evidence remains scattered across organ‐specific studies, and a focused synthesis across the genitourinary system is still lacking. This review summarizes the expression patterns, upstream regulators, downstream effects, and translational relevance of FASN in major genitourinary organs, with emphasis on the bladder, kidney, prostate, cervix, and ovary, as well as selected benign disorders. We also review current therapeutic strategies, including direct FASN inhibition, modulation of upstream lipogenic pathways, nanodelivery approaches, and rational combination regimens with chemotherapy, endocrine therapy, or immunotherapy. Available data support FASN as a shared metabolic node linking lipid reprogramming to both malignant progression and organ injury. In bladder, renal, prostate, and cervical cancers, FASN contributes to proliferation, invasion, metastasis, and treatment resistance. In renal and reproductive disorders, it is also involved in lipid deposition, inflammation, fibrosis, and ovulatory dysfunction. Despite promising preclinical findings, major challenges remain, including limited evidence in benign disease, marked mechanistic heterogeneity across organs, and insufficient clinical validation of biomarkers and targeted agents. A more integrated understanding of FASN may improve biomarker development and support metabolism‐based precision therapy in genitourinary disease.
ABSTRACT Viral infections of the central nervous system (CNS) pose a significant risk for seizures, and in some cases, long‐term epileptogenesis. Seizure development following viral infection involves diverse CNS mechanisms, with emerging evidence that peripheral factors, including gut microbiome composition and immune‐inflammatory responses, also contribute. The gut microbiome is a multifaceted ecosystem with important roles in CNS health, and advances in sequencing have enabled investigation of host and microbial genomic changes associated with seizure development. While both animal and human studies link gut dysbiosis to epilepsy, including infection‐induced epilepsy, the specific effects of viral‐induced seizures on the gut microbiome remain unclear. Moreover, the influence of virus‐triggered epileptogenesis is not well understood. This review summarizes current knowledge on viral infections linked to seizures and highlights the limited but growing evidence for gut microbial changes in this context. We focus on Zika virus (ZIKV), West Nile virus (WNV), and herpes simplex virus‐1 (HSV‐1), all implicated in human epileptogenesis, though direct microbiome–seizure connections are still limited. We also discuss severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), which causes neurological symptoms without consistently inducing seizures in rodent models despite neurological involvement, and Theiler's murine encephalomyelitis virus (TMEV), a murine virus widely used as a model of infection‐induced seizures because it induces strain‐dependent seizures in mice. Current evidence suggests associations among viral infections, gut microbiome alterations, and seizure occurrence; however, further causative studies are needed to define their roles and elucidate underlying mechanisms.
ABSTRACT Alzheimer's disease (AD) remains a major global health challenge, with a high rate of clinical trial failures often attributed to the limited translational predictive value of traditional experimental models. In vitro systems, ranging from induced pluripotent stem cell (iPSC)‐derived neurons to complex three‐dimensional (3D) organoids, have emerged as promising alternatives to investigate disease mechanisms in a controlled experimental setting. However, their rapid expansion has generated fragmented nomenclature and heterogeneous classification schemes. In this systematic review, we propose a hierarchical framework that categorizes in vitro AD models according to their architectural complexity and the biological questions they are designed to address. We organize these platforms into four progressive tiers: genetically defined iPSC‐derived cell‐autonomous models, stimulus‐based reductionist models, interaction‐dependent neuron–glia co‐cultures, and advanced multicellular 3D or neurovascular platforms. Our findings indicate that low complexity models (Tier 1 and Tier 2) are particularly suited to dissect cell‐intrinsic genetic drivers and acute toxic signaling, but they often fail to capture the chronic multicellular feedback loops and vascular dysfunction characteristic of AD. In contrast, high‐complexity systems (Tier 3 and Tier 4), including organ‐on‐chip platforms and vascularized organoids, provide the spatial and physiological context necessary to model neuroinflammation and network‐level degeneration, although they present greater technical variability. Finally, we propose an integrative hierarchical strategy that aligns model selection with specific pathological questions. By linking cellular complexity with mechanistic objectives, this framework provides a structured roadmap to improve experimental rigor, facilitate cross‐study comparability, and support the development of more predictive experimental models for AD.
Quality control (QC) processes include a network of cellular pathways that prevent the accumulation of toxic aggregates by repairing, recycling, and/or eliminating defective components, including mitochondria. Among these pathways are the proteostasis network, which regulates the proteome, and mitochondrial quality control (MQC) mechanisms, which maintain mitochondrial number and integrity. QC relies on a hierarchically and spatially integrated regulatory axis rather than individual parallel units. Such systems coordinate mitochondrial biogenesis, dynamics, and autophagic recycling with proteostasis to ensure the maintenance of high-quality mitochondria and bioenergetically efficient cells. Neurons, post-mitotic cells with high energy demands, depend heavily on these mechanisms and on the spatial coordination of MQC. Here, we discuss how failure of this integrated QC axis, rather than dysfunction of its individual components alone, can drive neuronal decline and contribute to the neurodegeneration.
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a context-dependent dual role in tumor immunity and immunotherapy. On one hand, it can act as an immunogenic cell death mechanism, releasing damage-associated molecular patterns that activate dendritic cells and promote T cell priming. On the other hand, ferroptosis may suppress antitumor immunity by triggering death or dysfunction in key immune cells, including T lymphocytes, dendritic cells, and macrophages. This review synthesizes current insights into the molecular determinants of ferroptosis sensitivity within the tumor microenvironment. It examines how immune cells can induce ferroptosis in cancer cells, and how tumors evolve resistance through upregulation of proteins like GPX4 and FSP1 or metabolic rewiring. The interplay between ferroptosis and immunity offers promising therapeutic avenues, such as combining ferroptosis inducers with immune checkpoint inhibitors or employing nanotechnology for targeted delivery. However, the net immunogenic outcome depends on temporal, cellular, and microenvironmental factors. Future strategies must aim to selectively induce immunogenic ferroptosis in tumors while preserving immune cell function, leveraging biomarkers and microenvironment modulation to optimize combination therapies in cancer immunotherapy.
