Review
Abstract
Sepsis is a systemic vascular disorder in which endothelial activation, dysfunction, and structural injury contribute to shock, microcirculatory failure, immunothrombosis, and multiorgan dysfunction. Sepsis-associated endotheliopathy is not a uniform process but a dynamic trajectory that evolves from adaptive endothelial activation toward functional disruption, structural injury, and organ-specific vascular failure. In this Review, we propose a phenotype- and trajectory-oriented framework that integrates clinical manifestations, molecular mechanisms, and translational assessment of endothelial dysfunction in sepsis. We focus on four major clinically recognizable modes of endothelial dysfunction that often overlap and evolve over the course of sepsis. We further discuss biology-anchored biomarker panels, bedside physiological surrogates, and serial trajectory-based assessment as complementary approaches for identifying endothelial states, refining risk stratification, and guiding future precision strategies. Finally, we describe implications for biomarker-enriched clinical trials, microvascular-informed resuscitation, and endotype-guided endothelial cell–targeted therapies. Viewing sepsis through the lens of dynamic endotheliopathy provides a framework linking vascular biology to clinically interpretable trajectories and may facilitate the development of personalized approaches to endothelial cell–directed care.
Authors
Song Qin, Ninan Dai, Fengyun Xu, Cindy Zhuang, Judith Hellman
Abstract
Most neurodegenerative diseases reflect patient-specific combinations of polygenic risk variants interacting with aging and environmental factors, rather than a single causative mutation. Phase III clinical trial failure rates for neurodegenerative indications exceed 95%, reflecting in part the limitations of existing preclinical systems to fully model the human genetic context of disease. Patient-derived induced pluripotent stem cells (iPSCs) have the potential to address this shortcoming by faithfully recapitulating human cell biology and preserving each patient’s complete genetic architecture. This Review examines iPSC-based models of neurodegeneration across three themes. First, we discuss mechanisms revealed by these models, from convergent pathways uncovered by familial mutations to early evidence that sporadic disease biology is accessible at sufficient cohort scale. Second, we evaluate culture systems from 2-dimensional monocultures to organoids, examining how increasing complexity expands addressable biological questions while introducing trade-offs. Third, we address the aging problem: reprogramming erases epigenetic signatures of donor aging, removing the cellular context in which late-onset sporadic neurodegeneration emerges. We discuss strategies approximating aging in iPSC-derived neurons and highlight direct conversion strategies that preserve native epigenetic age, enabling access to age-dependent phenotypes. We propose a framework matching model systems to biological questions, improving mechanistic understanding and therapeutic development.
Authors
Shijie Wang, Lisa Elia, Weiyi Liu, Steven Finkbeiner
Abstract
Preclinical drug development has long relied on animal models to predict safety and efficacy before agents enter human trials, despite critical differences between human and animal model physiology. The withdrawal of rosiglitazone, rofecoxib, and terfenadine due to cardiovascular toxicity exemplifies the translational cost of this mismatch. Alternative, human-based systems enable more accurate modeling of cardiometabolic diseases in a dish; in 2025, the US FDA’s new approach methodologies (NAMs) roadmap authorized the submission of results from human-relevant models. The roadmap encourages utilizing biological and digital twins as part of an integrated, context-specific, fit-for-purpose strategy. A “biological twin” is a human-derived in vitro system that captures the physiology of a patient and can be used to assess potential cardiotoxicity by drug metabolites. A “digital twin” is the computational counterpart trained on clinical drug response results that can further interpret biological twin data at the patient scale and predict pharmacological parameters. NAMs are no longer experimental but are not yet fully validated as replacements for animal models; major challenges remain before they can be effectively incorporated into the cardiometabolic disease drug discovery pipeline. Addressing these challenges head-on is essential for improving drug development and prediction of their cardiovascular safety.
Authors
Debarun Patra, Ibrahim M. Sayed, Ravichandra Venkateshappa, Latha Palaniappan, Tracey McLaughlin, Joseph C. Wu
Abstract
Ferroptosis is a distinct form of regulated cell death driven by lipid peroxidation and redox imbalance. Since its formal recognition in 2012, ferroptosis has emerged as a central pathway linking metabolic stress and oxidative injury to both physiologic and pathologic processes. Its functions extend from tissue sculpting during embryogenesis and tumor suppression to pathologic contributions in neurodegeneration, cardiovascular disease, liver and kidney injury, cancer, and inflammatory disorders. Despite these advances in our understanding of ferroptosis, critical questions remain regarding its precise regulation, context-specific consequences, and interactions with other cell death pathways. Continued progress in identifying biomarkers, defining context-specific roles, and developing selective modulators will be essential to translate ferroptosis biology into clinical therapies with broad impact. Here, we describe the current state of our understanding of the role of ferroptosis in physiology and its potential as a target mechanism in heart and kidney disease.
Authors
Simar J. Singh, Baljash Cheema, Hossein Ardehali
Abstract
Rare monogenic subtypes of migraine with aura, which include an autosomal dominant form of hemiplegic migraine (HM), are caused by exonic mutations whose functional consequences can be studied in cellular and animal models of the disease. This allows investigation of the neurobiological mechanisms at the molecular, cellular, and circuit level. Here, I review current knowledge of the genetics and pathophysiology of HM. After considering the genes whose mutations cause familial HM (FHM) and discussing how the encoded proteins are affected by the mutations, I consider the mouse models generated by introducing human FHM mutations in the orthologous genes, Cana1a, Atp1a2, and Scna1a. I discuss their phenotypes, highlighting their shared increased susceptibility to experimentally induced cortical spreading depression (CSD, the phenomenon which underlies migraine aura and may trigger the headache mechanisms) and migraine-relevant pain behaviors. I examine the alterations in the cerebral cortex and the mechanisms underlying the facilitation of CSD in the mouse models as well as the alterations in the trigeminovascular pain pathway and their possible contributions to migraine-relevant pain phenotypes. Finally, I discuss the translational implications of the pathogenic mechanisms of CSD facilitation.
Authors
Daniela Pietrobon
Abstract
γδ T cells are a subset of lymphoid cells that, unlike their αβ lineage counterparts, express a heterodimeric TCR that mostly operates in an MHC-independent manner. γδ T cells are abundant in barrier tissues, where they continuously monitor epithelial cells for signs of stress or damage. Thus, γδ T cells are among the first responders to pathophysiological conditions, including viral infection and oncogenesis. Human γδ T cells can be classified based on TCR γ and δ chain usage into three main subsets: (a) Vγ9+Vδ2+ cells, accounting for most circulating γδ T cells; (b) Vδ1+ cells, which are common in epithelial linings, and (c) Vδ3+ T cells, which are fairly rare but exhibit unique specificities. Moreover, both human and murine γδ T cells can assume a spectrum of states with divergent phenotypic and functional properties. Accumulating evidence demonstrates that γδ T cells can mediate robust anticancer effects or support tumor progression and resistance to therapy, depending on numerous variables, including functional state and tumor type. Here, we critically discuss the context-dependent interaction between γδ T cells and cancer, focusing on recent developments and the challenges facing current efforts to manipulate this versatile lymphocyte subset for therapeutic purposes.
Authors
Lukas Bolini, Seth B. Coffelt, Bruno Silva-Santos, David L. Wiest, Lorenzo Galluzzi
Abstract
Heart transplantation remains the gold standard therapy for patients with end-stage heart failure. However, post-transplant complications are considerable. Emerging evidence implicates the gut microbiome as a modifiable determinant of post–heart transplant outcomes through its influence on host immunity, metabolism, and inflammation. This Review synthesizes current understanding of gut microbiome dysregulation following solid organ transplantation, with particular emphasis on heart transplantation, examining mechanistic links underpinning important complications including allograft rejection, infection, metabolic dysfunction, and cardiac allograft vasculopathy. We critically evaluate bidirectional interactions between the gut microbiome and immunosuppressive drugs, assess the potential for microbiome profiling to serve as a predictive biomarker for post-transplant complications, and examine microbiome-targeted interventions including dietary modification, prebiotics, probiotics, and fecal microbiota transplant. Finally, we propose a translational roadmap to integrate microbiome science into heart transplant care to optimize immunosuppression, predict complications, and improve long-term outcomes for heart transplant recipients.
Authors
Ivan Ðuran, W.H. Wilson Tang, Petra Mamic
Abstract
Synergizing radiotherapy (RT) with immune checkpoint inhibitors has emerged as a promising strategy for solid tumors. RT acts as a potent immunomodulator, capable of functioning as an in situ vaccine through the induction of immunogenic cell death and activation of innate immune sensing, thereby promoting DC maturation and CD8+ T cell responses. However, RT also triggers counter-regulatory immunosuppression, including PD-L1 upregulation and the recruitment of suppressive cells, providing the biological rationale for synergy. Here, we systematically review advances in radioimmunotherapy, covering immunomodulatory mechanisms, clinical optimization of dose and sequencing, and the emerging role of artificial intelligence (AI) in guiding treatment paradigms. We adopt a spatial interaction–centric perspective to synthesize current knowledge on how RT governs the DC/CD8+ T cell interaction axis across the tumor microenvironment and tumor-draining lymph nodes, aiming to chart a rational course from empirical combination toward personalized, precision radioimmunotherapy. Furthermore, we explore how AI-driven analysis of radiomics and multiomics data is being applied to predict responders and personalize treatment planning.
Authors
Lu Lu, Liufu Deng
Abstract
Protein neddylation is an evolutionarily conserved posttranslational modification that conjugates NEDD8 to its substrate, catalyzed by an E1-activating enzyme, E2-conjugating enzyme, and E3 ligase. Neddylation is essential for cellular homeostasis, and its dysregulation has been implicated in diverse human diseases, including cancer, neurodegenerative diseases, and metabolic disorders, making the process a promising therapeutic target. In this Review, we systematically summarize the biochemical activity and biological functions of neddylation; its alterations in human diseases, particularly in cancers; and its validation as an attractive target for cancer therapy. We provide an overview on the discovery of neddylation inhibitors and the progress of MLN4924 (pevonedistat) and TAS4464 clinical trials and critically evaluate the core challenges and emerging opportunities for therapeutic strategies targeting neddylation.
Authors
Shizhen Zhang, Huiyin Lan, Yi Sun
Abstract
Beyond serving as a structural organ, the skeleton undergoes continuous remodeling and functions as an endocrine organ by secreting bioactive factors that regulate the physiology of distant tissues. Indeed, the concept of a “bone-vascular axis” has long been recognized, supported by epidemiological evidence linking osteoporosis and low bone mass to increased cardiovascular morbidity and mortality. Emerging findings now extend this paradigm to the brain, suggesting that bone- and bone marrow–derived signals influence cerebrovascular structure, function, and aging. Given that cerebrovascular dysfunction is a central driver of age-related cognitive decline, dementia, and neurodegenerative diseases, understanding this “bone-cerebrovascular axis” may offer novel opportunities for prevention and intervention. Here, we outline the cellular and molecular mechanisms underlying age-associated neurovascular impairment and summarize the biology of major bone and bone marrow cell populations, with emphasis on age-related alterations in their secretome. A central focus of this Review is the emerging evidence that age-related skeletal alterations exert systemic effects on the cerebrovasculature, highlighting how bone- and bone marrow–derived factors shape neurovascular health and pathology, which may subsequently contribute to CNS aging and neurodegeneration. A deeper understanding of these systemic interactions reframes brain aging within a whole-body context and may uncover innovative biomarkers and therapeutic strategies to mitigate neurodegeneration and other age-associated disorders.
Authors
Jiekang Wang, Xu Cao, Mei Wan
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Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)