In a recent Science study, Shenoy et al. reveal that maternal milk IgG programs neonatal immunity in mice. During the first postnatal week, IgG forms complexes with gut microbes, calibrating T cell responses at weaning and establishing long-term tolerance, uncovering a critical early-life window that shapes lifelong immune function.

Peptide-ionizable lipids (PILs) establish a rational design paradigm for RNA delivery, defining a chemical code that programs organ tropism and enables systemic prime editing. By achieving precise mRNA and genome editing beyond the liver, this platform opens a new era of multi-organ RNA therapeutics and precision genetic medicine.

The hypothalamus is a central regulator of circadian rhythms, metabolism, and endocrine function, integrating internal and external cues to maintain physiological homeostasis. Aging impairs hypothalamic function, leading to metabolic changes, sleep disturbances, and a higher risk of age-related disease. Laminopathies - rare genetic disorders marked by premature aging - exhibit profound neuroendocrine and circadian rhythm dysfunction, offering insights into mechanisms of hypothalamic aging. The complex interplay between the hypothalamus, circadian rhythms, and systemic aging highlights the critical role of neuroendocrine crosstalk in the regulation of health span and life span. This review summarizes emerging molecular and physiological insights into hypothalamic aging and circadian misalignment, and highlights potential interventions, such as chronotherapy and caloric restriction, that may alleviate hypothalamic alterations and promote healthy aging.

Microbial pathogens have developed diverse strategies to exploit the host immune system because of their long period of coevolution with the target hosts. A deeper understanding of these mechanisms, particularly the role of microbial virulence proteins (MPs) in modulating host immune defense mechanisms, has opened new avenues for devising innovative therapeutic strategies. Several MPs are now being repurposed for the treatment of a range of clinical conditions including anti-inflammatory, anticancer, antimicrobial, antithrombotic, antidiabetic, and kidney-related diseases. Some of these therapies are currently in clinical trials or in clinical use. This review highlights recent advances in repurposing MPs as therapeutics and their growing clinical relevance.

Men have a higher incidence of specific types of cancer and neurodegenerative disease. Mounting evidence suggests that androgen receptor (AR)-mediated androgen signaling is a key determinant at the core of this sex discrepancy. Herein we review the role of androgens in disorders characterized by altered AR activity, focusing on transcriptional coregulators that shape receptor specificity. In particular, we highlight the roles of protein arginine methyltransferase 6 (PRMT6) and lysine-specific demethylase 1 (LSD1), enzymes associated with epigenetic repression, yet functioning as AR coactivators. By enhancing AR transcriptional output, PRMT6 and LSD1 contribute to malignant transformation and progression across multiple cell types. We further explore how these insights inform combinatorial therapeutic strategies targeting AR, PRMT6, and LSD1, with implications for both cancer and neurodegeneration.

Iron, regulated by the hormone hepcidin, is essential for cellular function and diverse biological processes. In this forum, we examine emerging therapeutic approaches targeting the hepcidin-iron axis, with applications across three key areas: cancer treatment, polycythemia vera (PV) and anemia, and infectious disease.

Leptomeningeal metastasis (LM) represents a devastating and terminal complication of advanced solid tumors, characterized by the dissemination of malignant cells within the leptomeninges and cerebrospinal fluid. Conventional therapies have demonstrated limited efficacy due to substantial toxicity and poor drug penetration. Recent advances in targeted therapy, immunotherapy, and intrathecal drug delivery are reshaping the therapeutic landscape for LM. Brain-penetrant agents have shown improved outcomes, and intrathecal administration of antibodies and immune checkpoint inhibitors (ICIs) further expands therapeutic options. Immunotherapies, notably chimeric antigen receptor T cells (CAR-T cells) and mesenchymal stem-cell-based therapies offer promise in counteracting LM's immunosuppressive microenvironment. These innovations represent a paradigm shift in the management of LM and offer a renewed therapeutic potential for patients with LM. This review highlights key preclinical and clinical advances that are reshaping the management of LM.

Hosts have evolved multifaceted, intricate mechanisms to sense and respond to the microbes they coexist with, and these mechanisms play an important role in health and disease. The co-metabolism of dietary components by hosts and their microbiomes produces a myriad of signaling molecules, which are increasingly recognized in pathophysiology regulation via their engagement with the neuro-immune network. In this review, we focus on the emerging role of tryptophan (Trp) metabolites in host-microbe crosstalk through the lens of neuroimmune sensing in the gut and beyond. We highlight how Trp metabolites orchestrate the immune and neural networks to mediate the local and trans-organ effects of the microbiome. We also consider how a neuroimmunometabolic perspective could offer valuable insights into the pathogenesis of, and treatment strategies for, chronic diseases.

Aging is the gradual decline in physiological function essential for survival and reproduction. Unlike age-associated diseases, aging affects all individuals within a species, causing progressive impairments across multiple systems. Research shows that altering specific genes or dietary factors can extend lifespan, implicating molecular pathways in controlling senescence. Chronological age (CA) is a common measure of aging, but other hallmarks like telomere shortening better quantify functional decline. Identifying age-related hallmarks can help manipulate aging, spurring interest in aging clocks. These clocks predict biological age (BA) more precisely than CA, reflecting actual physiological health. As global life expectancy continues to rise, aging clocks hold promise for developing therapies to extend healthspan and improve life quality during aging.

Despite revolutionary molecular targeting therapies introduced over the past two decades for the management of inflammatory bowel disease (IBD), there remains significant variability in drug efficacy, which likely reflects the multifactorial basis and the complex and dynamic nature of the disorder. The presence of different molecular mechanisms and the diversity of cytokine expression profiles that drive distinct subtypes or different phases of IBD could affect the response to current pharmacological treatments. In this review we discuss the distinct roles of cytokines across different disease phases, and emphasize the importance of tailored drug use based on available biomarkers to deliver molecular targeted agents suited to the condition of each patient.

The Integrator complex, composed of at least 19 subunits, associates with RNA polymerase II (RNAPII) and exerts critical roles in transcriptional regulation. By interacting with the C-terminal domain (CTD) of RNAPII, it cleaves nascent RNA transcripts, leading to termination of non-productive transcription in protein-coding genes and processing of diverse noncoding RNAs. Beyond RNA cleavage, Integrator regulates transcription initiation, pause-release, and elongation, while also processing enhancer RNAs. It contributes to genome stability by modulating RNAPII activity during DNA damage and replication stress. Dysfunction of Integrator subunits has been linked to neurodevelopmental disorders and cancer, underscoring its broad physiological significance. This review highlights recent advances in structure and function that illuminate Integrator's essential roles in development, neurobiology, and disease.

Hyaluronan synthases (HASs) are essential enzymes for hyaluronic acid (HA) production; a key component for joint lubrication and cartilage health. Dysregulated HA synthesis contributes to joint dysfunction. In this Forum, we discuss the role of HAS in matrix assembly, inflammation and the pathogenesis of osteoarthritis (OA).

Emerging evidence highlights the brain renin-angiotensin system (RAS) as a key regulator of reward, memory, and stress. While these discoveries established the brain RAS as a promising therapeutic target for interventions in neurological and neuropsychiatric disorders, translational progress is hampered by the lack of an integrative mechanistic framework. Here, we consolidate accumulating evidence on the molecular and system-level roles of the brain RAS in reward, memory, and stress pathways, and its dual regulatory architecture. Pharmacological RAS modulation regulates domain-specific signaling in frontostriatal reward circuits, hippocampal-prefrontal memory networks, and frontolimbic fear networks. We evaluate the transdiagnostic therapeutic potential in neurological and neuropsychiatric disorders (e.g., dementia and depression), identify translational barriers, and conclude with strategic research priorities to facilitate clinical translation.

The oxidative stress paradigm stands as a textbook example of how a simplified, early, and appealing scientific concept can become canonized and then resist revision. What began as a plausible heuristic about oxidative stress evolved into a research agenda and a pervasive cultural script.

Two decades after the first recognition of anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, advances have led to consensus-based diagnostic criteria and treatment recommendations, yet no FDA-approved therapies exist. Recent studies highlight limitations of serum-only antibody testing, importance of tailored tumor surveillance, and epidemiologic variation across racial and ethnic groups. Prognostic indicators, exemplified by the anti-NMDAR encephalitis 1-year functional status (NEOS) score, have refined outcome prediction. Although nearly 80% of patients achieve favorable functional outcomes, persistent neuropsychiatric and cognitive deficits may impact quality of life, highlighting the need for improved therapeutic strategies. Accordingly, randomized clinical trials are underway, including studies evaluating B cell- and interleukin-6 (IL-6)-targeted therapies, for anti-NMDAR encephalitis. This review synthesizes these developments and discusses current treatment approaches with a focus on emerging investigational therapies.

Metastasis remains a major contributor to the poor prognosis for patients with cancer, primarily driven by dynamic interactions between cancer cells and the tumor microenvironment. Accumulating evidence highlights the pivotal involvement of both gut microbiota and intratumoral bacteria in cancer progression and metastatic spread. Here, we review the intricate links between microbiota and cancer metastasis, elucidating the multifaceted mechanisms by which microbial communities modulate metastatic processes. We particularly focus on the role of microbial metabolites in cancer dissemination and discuss innovative therapeutic strategies targeting the microbiome. Targeting the gut microbiota and intratumoral microecology presents a promising avenue for novel interventions aimed at mitigating cancer metastasis.

Bhatt et al. have identified two RNAome-based skeletal muscle subtypes in cancer cachexia. The first subtype is cachexia associated with weight and muscle loss, fiber atrophy, and shortened survival. Furthermore, this subtype has dysregulated post-transcriptional networks involving hub long noncoding (lnc)RNAs, neuronal, immune, and metabolic pathways. The study highlights new biomarkers and network-targeted interventions.

Pediatric acute megakaryoblastic leukemia (AMKL) associated with the CBFA2T3::GLIS2 (CG2) gene fusion is distinctive by virtue of its aggressiveness and ability to transform normal cells in a single event. The dismal therapeutic response of children to this disease has stimulated comprehensive studies on the molecular mechanism of CG2-driven tumorigenesis. In this Opinion, we highlight various investigative strategies, used in parallel by multiple independent research teams, that point to a specific dependence of CG2-expressing leukemias on the B cell leukemia/lymphoma-2 (BCL-2) family of antiapoptotic proteins. We propose that this intrinsic feature renders these leukemias particularly vulnerable to BCL-2 homology 3 (BH3) mimetics.

The angiopoietin-like protein (ANGPTL)3/8 complex regulates triglyceride partitioning, and its selective blockade lowers triglycerides while raising HDL-cholesterol (HDL-C). Clinical and genetic evidence support ANGPTL3/8 antagonism as a precision therapy for mixed dyslipidemia, monogenic hypertriglyceridemia (CREBH or APOA5 deficiency), and diabetic dyslipidemia by correcting a fundamental disturbance in lipid partitioning.

Endometriosis, traditionally viewed as a gynecological condition, is increasingly recognized as a systemic disease due to its frequent association with inflammatory and autoimmune comorbidities. Recent molecular and genetic insights reveal dysregulated hormone receptor signaling, heightened inflammatory responses, and immune dysfunction as central drivers of disease progression. These discoveries offer compelling explanations for extra-pelvic symptoms and open up avenues for targeted diagnostics and therapies. This review integrates emerging evidence to highlight endometriosis as a multisystem disorder, underscoring the need for multidisciplinary care. By redefining endometriosis beyond reproductive health, this perspective encourages a broader, systemic view of women's health and fosters innovation in precision medicine.

Precision medicines for monogenic brain disorders are rapidly advancing. Voltage-gated sodium channel (VGSC) genes are the leading monogenic cause of severe epilepsy and profound autism spectrum disorder (ASD), most notably SCN1A, SCN2A, SCN3A, and SCN8A. Recent advances in animal and human induced pluripotent stem cell (hiPSC) disease models provide a powerful platform for advancing precision medicines. Thanks to the genomic revolution, many gene therapies are in preclinical studies and clinical trials for VGSC-related diseases, including viral vector gene replacement, clustered regularly interspaced short palindromic repeats (CRISPR) base editing, prime editing, and genetic modulation strategies including antisense oligonucleotides, engineered tRNAs, and CRISPR activation/interference (CRISPRa/i). This review highlights the latest advances in disease modeling and next-generation therapeutic development to advance precision medicine for VGSC-related brain disorders.