Ticagrelor, a commonly used antiplatelet medication, has been found to exhibit considerable inter-individual pharmacodynamic variability. Recent studies have revealed a close relationship between pharmacokinetics and pharmacodynamics, both of which can be influenced by gut microbiota. In this study, we explored whether the pharmacokinetics of ticagrelor is mediated by intestinal flora. We enrolled 22 healthy participants to assess the clinical pharmacokinetic profiles of ticagrelor and its metabolite AR-C124910XX after a single oral dose of ticagrelor. The fecal microbial compositions of individuals who exhibited distinct pharmacokinetic parameters were analyzed using 16S rRNA gene sequencing. Additionally, we conducted experiments involving the co-incubation of ticagrelor with fecal bacteria and a systematic exploration of the pharmacokinetics of ticagrelor in pseudo-germ-free (PGF) rats to illustrate the role of gut microbiota in ticagrelor metabolism, both in vitro and in vivo. Our findings revealed a three-fold difference in the bioavailability of ticagrelor among individuals. However, no difference was found in the composition of gut microbiota among individuals with different pharmacokinetic parameters. Quantitative analysis showed that gut microbiota cannot directly metabolize ticagrelor. Furthermore, there were no significant differences in AUC(0-48), AUC(0-∞), and Cmax between ticagrelor and AR-C124910XX in PGF rats compared to normal control, either by single intragastric or intravenous administration. In conclusion, these findings suggest that gut microbiota has no impact on the pharmacokinetics of ticagrelor.

[This corrects the article DOI: 10.3389/fimmu.2026.1818835.].

Atherosclerosis (AS) poses major challenges for precise diagnosis and targeted therapy due to its complex inflammatory and oxidative plaque microenvironment. This review begins by dissecting the cellular and molecular hallmarks of AS progression, from endothelial dysfunction to plaque rupture, identifying key targets including adhesion molecules, scavenger receptors, and immune costimulatory pathways that can be exploited for nanotheranostic intervention. Rare-earth nanoparticles (RENPs) offer a versatile platform that integrates multimodal imaging with therapeutic functions. We highlight the strategic design of RENPs, including core-shell engineering, surface functionalization, and doping strategies, to enhance NIR-II luminescence, lifetime multiplexing, and X-ray-activated persistent luminescence for high-resolution vascular imaging and fluorescence-guided surgery. Their intrinsic enzyme-mimetic activities, particularly the cerium-based nanozymes that scavenge reactive oxidative species, are examined as a key therapeutic mechanism targeting oxidative stress within plaques. A critical discussion of biocompatibility analyzes the element- and form-dependent toxicity profiles, emphasizing the divergent effects between therapeutic nanomaterials and potentially harmful rare-earth ions. These insights underscore the necessity of rigorous safety evaluations alongside functional development. Finally, we outline future directions and challenges in the clinical translation of RENP-based theranostic strategies, emphasizing the need for optimized targeting, biosafety, and multifunctional integration to achieve the precise diagnosis and effective treatment of atherosclerotic cardiovascular diseases.

Growth differentiation factor 15 (GDF15) is a stress responsive cytokine belonging to the transforming growth factor-β (TGF-β) superfamily, serving as a sentinel of metabolic integrity. Its expression is induced by multiple convergent stress pathways, including the integrated stress response (ISR), endoplasmic reticulum (ER) stress, oxidative stress, inflammation, and hypoxia. GDF15 is secreted by a wide range of organs, such as adipose tissue, skeletal muscle, liver, heart, kidney, immune cells, and the central nervous system, with the relative contribution of each tissue varying across different physiological and pathological states. Through the hindbrain GFRAL-RET axis, GDF15 suppresses appetite and regulates energy balance, while also exerting peripheral effects on mitochondrial function, insulin sensitivity, and inflammatory responses. Transient GDF15 elevation in response to acute stressors supports adaptive metabolic resilience and tissue protection. In contrast, chronic and sustained elevation signals progressive metabolic dysfunction, organ impairment, and poor prognosis in conditions including obesity, metabolic dysfunction associated steatotic liver disease (MASLD), diabetes, and cardiovascular disease. Importantly, the biological impact of GDF15 is modified by factors such as age and metabolic context, which may shift the balance between adaptive and maladaptive outcomes and account for much of the predictive signal in clinical studies. Although GDF15 holds promise as a prognostic biomarker and a therapeutic target, its clinical translation is hindered by two major challenges: its dual protective and pathological roles, and an incomplete understanding of non-GFRAL signaling pathways. This narrative review summarizes the regulatory networks, tissue sources, and context-dependent functions of GDF15, with an emphasis on its roles in cardiometabolic homeostasis and the potential for future precision therapeutic strategies. We present the sentinel model as a working hypothesis that generates testable predictions, rather than as a proven biological mechanism. The acute-adaptive versus chronic-maladaptive distinction, while conceptually useful, requires validation through measurable parameters including concentration thresholds, temporal dynamics, and tissue specific contributions.

Mixed shock is common after cardiac arrest (CA), with dominant shock physiology sometimes changing over the course of hours. This article focuses on identifying dominant shock physiology in patients with refractory shock after CA and targeted strategies for resuscitation. The authors discuss approach to cardiogenic shock, including pharmacologic and mechanical support, as well as advanced pharmacologic therapies relevant to distributive shock.

Status epilepticus (SE) is a common neurological emergency in children, carrying significant risks of morbidity and mortality. Refractory SE (RSE) and super-refractory SE (SRSE) represent the most severe end of this spectrum and are among the most challenging clinical scenarios in pediatric neurology. This review addresses the key molecular and cellular mechanisms underlying the transition to refractoriness, including activity-dependent changes in GABAergic and glutamatergic neurotransmission and the activation of neuroinflammatory pathways, and discusses their implications for treatment. We further review current evidence on the pharmacological management of pediatric RSE and SRSE, from the rational use of sedating agents to less conventional strategies such as ketamine, the ketogenic diet, and immunomodulatory therapies. Understanding the pathophysiology of refractoriness is key to optimizing existing therapies and developing novel, mechanism-based approaches for children affected by this condition.

Ischemia and angina with non-obstructive coronary arteries (INOCA/ANOCA) have evolved into a defined clinical entity, with invasive coronary functional testing now guideline-recommended to establish the underlying endotypes. Yet diagnostic progress has outpaced pathophysiological understanding and therapeutic development. This article examines the principal unmet needs across INOCA/ANOCA: the observational nature of current registries; the unresolved molecular basis, natural history and overlap of the microvascular and vasospastic endotypes; persistent underdiagnosis and unstandardized invasive physiology; the absence of validated non-invasive tools and biomarkers; and the lack of endotype-targeted therapies proven to improve outcomes. Addressing these gaps is essential to advance mechanism-based personalized care.

Coronary dysfunction encompasses a spectrum of pathophysiologically distinct endotypes with differing therapeutic implications. The aim of this article was to provide an overview of device-based therapies targeting the various forms of coronary dysfunction. A systematic review of the available literature was performed. Multiple device-based strategies have been proposed for the treatment of angina in the absence of obstructive coronary artery disease, reflecting the heterogeneity of underlying mechanisms, and tailored approaches based on specific endotypes may improve symptom control and clinical outcomes.

Management of chronic coronary syndromes has shifted from an obstructive coronary artery disease-focused model to a phenotype-guided approach that includes angina with nonobstructive coronary arteries/ ischemia with nonobstructive coronary arteries (INOCA), vasospastic angina (VSA), and coronary microvascular dysfunction (CMD). Background therapies such as statins, angiotensin-converting enzyme inhibitors, antiplatelets, and sodium-glucose cotransporter-2 inhibitor inhibitors improve vascular health, but the WARRIOR trial highlighted the limits of intensive therapy in unselected INOCA patients. Anti-ischemic treatment should be mechanism-based: calcium channel blockers for VSA, beta-blockers and ranolazine for CMD, while nitrates may worsen microvascular disease.

Over 3 decades, invasive coronary physiology has evolved into a cornerstone of cardiovascular care. Fractional flow reserve (FFR) enabled lesion-specific assessment of epicardial stenoses, improving percutaneous coronary intervention (PCI) selection beyond angiography. Recognition of ischemia without obstructive disease expanded its role, with contemporary testing integrating adenosine-based flow assessment and acetylcholine-based evaluation of endothelial and vasomotor function, allowing identification of angina with nonobstructive coronary arteries endotypes, and tailored therapy. Physiologic pullback and post-PCI indices support procedural planning. Emerging tools, including angiography-derived indices, FFR-computed tomography, and optical coherence tomography (OCT)-based virtual flow reserve, are extending physiology-guided care toward noninvasive assessment and precision cardiovascular intervention.