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.

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.

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.

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.

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.

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.

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.

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.

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.

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, most (ASD) 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.

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.

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, most (ASD) 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.

Congenital urinary bladder outflow obstruction (BOO) is a major cause of kidney failure in children. Sometimes, it is caused by anatomical obstruction of the urethra. In other cases, functional failure of voiding occurs without anatomical obstruction. Bladder development is driven by genes expressed in smooth muscle, neural and urothelial cell lineages. Variants in the coding regions of such genes cause a subset of BOO. In other cases, such as posterior urethral valves (PUV), noncoding variants may influence susceptibility. By modelling BOO in mutant mice, combined with viral vector mediated gene therapy, steps are being made to ameliorate the pathobiology of these diseases. Translation of such strategies to humans may require prenatal gene therapy.

Congenital urinary bladder outflow obstruction (BOO) is a major cause of kidney failure in children. Sometimes, it is caused by anatomical obstruction of the urethra. In other cases, functional failure of voiding occurs without anatomical obstruction. Bladder development is driven by genes expressed in smooth muscle, neural and urothelial cell lineages. Variants in the coding regions of such genes cause a subset of BOO. In other cases, such as posterior urethral valves (PUV), noncoding variants may influence susceptibility. By modelling BOO in mutant mice, combined with viral vector mediated gene therapy, steps are being made to ameliorate the pathobiology of these diseases. Translation of such strategies to humans may require prenatal gene therapy.

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.

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.

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.

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.

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).

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).

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.