Robinson M, Wettschurack K, Halurkar MS
… +4 more, Chen X, Zhang Z, Zhang J, Yang Y
Trends Mol Med
· 2026 Apr · PMID 41162233
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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 nota...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.
Trends Mol Med
· 2026 May · PMID 41111013
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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 intervention...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.
Trends Mol Med
· 2025 Dec · PMID 41109822
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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...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...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).
Trends Mol Med
· 2026 Apr · PMID 41073164
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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...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.
Trends Mol Med
· 2025 Dec · PMID 41062342
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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 a...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.
Trends Mol Med
· 2026 May · PMID 41062341
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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 pi...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.
Hoshina Y, Smith TL, Wright MA
… +3 more, Day GS, Titulaer MJ, Clardy SL
Trends Mol Med
· 2026 May · PMID 41062340
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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 ex...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.
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 the...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.
Trends Mol Med
· 2026 Jan · PMID 41044014
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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 s...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.
Petraglia F, Vannuccini S, Donati C
… +3 more, Jeljeli M, Bourdon M, Chapron C
Trends Mol Med
· 2026 May · PMID 41038746
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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 gene...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.
Trends Mol Med
· 2026 Mar · PMID 41033872
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With the use of assisted reproductive technology to treat infertility, there has been an increase in the condition known as empty follicle syndrome (EFS). EFS is characterized by the failure to retrieve oocytes from mult...With the use of assisted reproductive technology to treat infertility, there has been an increase in the condition known as empty follicle syndrome (EFS). EFS is characterized by the failure to retrieve oocytes from multiple mature follicles despite normal follicle development following ovarian stimulation. Despite its clinical significance, there is a lack of comprehensive and up-to-date reviews on this syndrome. In addition, the borderline form of EFS, that is characterized by low oocyte retrieval rates and is more common in clinical practice, has not been extensively discussed. This review aims to update perspectives on EFS, and covers its classification, etiology, treatment, prediction, prevention, and prognosis with the goal of leading to better clinical management and future research that improves outcomes for infertility patients.
Wolf A, Leardini D, Li L
… +3 more, Masetti R, Lyssiotis CA, Barbieri E
Trends Mol Med
· 2026 Feb · PMID 40993020
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Oncogenic MYCN drives aggressive disease in many cancers including neuroblastoma (NB). Metabolic reprogramming is essential to support cancer cell homeostasis and survival under nutrient- and oxygen-deprived conditions....Oncogenic MYCN drives aggressive disease in many cancers including neuroblastoma (NB). Metabolic reprogramming is essential to support cancer cell homeostasis and survival under nutrient- and oxygen-deprived conditions. MYCN directly reprograms many nodes of tumor-intrinsic metabolism, which have significant repercussions on the cells of the tumor microenvironment (TME), resulting in complex intercellular metabolic circuits that contribute to the immunosuppressive microenvironment of NB. These metabolic circuits are also regulated by the organismal and cellular circadian clock and host diet to further impact the TME and NB oncogenesis. This review discusses the mechanisms by which MYCN regulates the metabolic crosstalk between tumor, TME, and host, and provides evidence that therapeutic targeting of MYCN-reprogrammed metabolism can improve patient outcomes.
Nassini R, Chieca M, Marini M
… +2 more, Landini L, De Logu F
Trends Mol Med
· 2026 Jan · PMID 40973556
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Chronic pain affects millions of people worldwide and represents a crucial public health issue. A growing body of preclinical evidence suggests that adeno-associated virus (AAV) vectors are a powerful gene therapy tool f...Chronic pain affects millions of people worldwide and represents a crucial public health issue. A growing body of preclinical evidence suggests that adeno-associated virus (AAV) vectors are a powerful gene therapy tool for chronic pain management. We systematically summarize how AAV vectors, by targeting molecular pain pathways in neuronal and non-neuronal cells, may offer precise and sustained pain relief. We provide an overview of the latest findings and emerging concepts in this area, and discuss preclinical innovations in neuropathic, inflammatory and cancer-related pain. We also present clinical data on pain modulation by AAV in osteoarthritis (OA) patients. Finally, we provide a thorough analysis of key concerns about AAV therapy, including potential immune responses, toxicity, and adverse effects.
Increased understanding of the pathophysiology of migraine has resulted in the development of therapies targeting calcitonin gene-related peptide and its receptor. Ditans, which are serotonin 5HT receptor agonists, have...Increased understanding of the pathophysiology of migraine has resulted in the development of therapies targeting calcitonin gene-related peptide and its receptor. Ditans, which are serotonin 5HT receptor agonists, have demonstrated efficacy in acute management and bypass vascular risks associated with triptans, which are 5HT receptor agonists. However, despite favourable safety and efficacy data, many patients do not respond to these therapies. Treatments targeting pituitary adenylate cyclase activating polypeptide and other potential targets, including amylin and adrenomedullin and their receptors, K and transient receptor potential ion channels, as well as neuronal nitric oxide synthase, are emerging. Improving our understanding of patient heterogeneity in migraine biology may pave the way for precision medicine in migraine management.
Trends Mol Med
· 2025 Oct · PMID 40935730
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It is well established that pseudouridine (Ψ) and its derivative N-methylpseudouridine (mΨ) suppress unwanted immunogenicity of RNA-based therapeutics. However, molecular mechanisms governing such immune evasion remain e...It is well established that pseudouridine (Ψ) and its derivative N-methylpseudouridine (mΨ) suppress unwanted immunogenicity of RNA-based therapeutics. However, molecular mechanisms governing such immune evasion remain elusive. In a recent article, Bérouti, Wagner, and colleagues show that Ψ impairs the processing of Toll-like receptor (TLR)-agonistic ligands and hinders TLR activation.
Trends Mol Med
· 2026 Mar · PMID 40930855
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Ferroptosis, a regulated cell death pathway driven by iron-catalyzed lipid peroxidation, has recently been implicated as a major cause of hepatic injury in metabolic dysfunction-associated fatty liver disease (MAFLD). Th...Ferroptosis, a regulated cell death pathway driven by iron-catalyzed lipid peroxidation, has recently been implicated as a major cause of hepatic injury in metabolic dysfunction-associated fatty liver disease (MAFLD). This review highlights how the identification of hyperoxidized peroxiredoxin 3 (PRDX3) as a ferroptosis-specific marker has led to the discovery that ferroptosis contributes to liver injury in MAFLD, and summarizes other emerging evidence connecting ferroptosis to MAFLD pathogenesis. These new findings suggest that dietary fat composition and genetic variants such as PNPLA3(I148M) may affect the progression of MAFLD by regulating cellular sensitivity to ferroptosis. Recognizing MAFLD as a ferroptotic disease provides novel insights into the pathogenesis of the disease, and supports the exploration of ferroptosis as a potential target for therapeutic intervention.
Schanbacher C, Goebeler ME, Gerull B
… +1 more, Lorenz K
Trends Mol Med
· 2026 Mar · PMID 40914707
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Dysregulation of the RAF-MEK-ERK1/2 pathway is involved in the pathoetiology of many diseases. Its central role in cancer has led to the development of drugs targeting upstream receptors, RAS, and kinases in the extracel...Dysregulation of the RAF-MEK-ERK1/2 pathway is involved in the pathoetiology of many diseases. Its central role in cancer has led to the development of drugs targeting upstream receptors, RAS, and kinases in the extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2) signaling cascade. The use of these drugs in cancer therapy - together with ongoing monitoring of their effectiveness, evolving side-effects, and resistance mechanisms - has expanded our knowledge of both the physiological and pathological functions of ERK1/2 and could thus provide potential alternative therapeutic strategies. In this review we discuss the latest insights into targeting of MEK1/2 and ERK1/2 and the transfer of the lessons learned from cancer treatment to further indications involving ERK1/2 dysregulation such as genetic disorders (RASopathies) and beyond.
Escopete S, Arzt M, Mozneb M
… +2 more, Moses J, Sharma A
Trends Mol Med
· 2026 Mar · PMID 40914706
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Cardiac organoids are 3D self-assembling structures that recapitulate some of the functional, structural, and cellular aspects of the developing heart. Cardiac organoid modeling has overcome many of the limitations of cu...Cardiac organoids are 3D self-assembling structures that recapitulate some of the functional, structural, and cellular aspects of the developing heart. Cardiac organoid modeling has overcome many of the limitations of current cardiac modeling systems by providing a human-relevant, multicellular, spatially advanced model that can replicate early key developmental stages of human cardiogenesis. Recent advancements in cardiac organoid modeling have enabled further understanding of cardiogenesis, cardiovascular disease, and drug-induced cardiotoxicity. Emerging tools to effectively characterize cardiac organoid models to understand their morphology, function, and cellular phenotype will enable further understanding of cardiac development, cardiovascular disease, and preclinical drug discovery.
Han S, Chen Z, Wang D
… +21 more, Jiang L, Fan X, Zhong J, Cui C, Chen Y, Lv J, Zhang J, Zhao Y, Shi D, Lu W, Chen S, Jiang H, Yuan W, Wang Q, Feng G, Liu X, Yuan H, Zeng FG, Li H, Chen ZY, Shu Y
Trends Mol Med
· 2026 Mar · PMID 40908193
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Recent breakthroughs in gene therapy for autosomal recessive deafness 9 (DFNB9) caused by OTOF mutations have transformed treatment paradigms for hereditary hearing loss (HHL). To date, eight clinical trials targeting DF...Recent breakthroughs in gene therapy for autosomal recessive deafness 9 (DFNB9) caused by OTOF mutations have transformed treatment paradigms for hereditary hearing loss (HHL). To date, eight clinical trials targeting DFNB9 have been registered in 51 centers across eight countries, demonstrating the rapid progress of gene therapy in auditory medicine. These pioneering studies establish the framework for the clinical translation of gene therapy targeting HHL. This review synthesizes progress in OTOF-related clinical trials, highlighting translational foci such as inner ear drug delivery, trial design, safety assessments, and auditory restoration outcomes. Key challenges in optimizing future therapeutic strategies - including addressing anatomical constraints, refining patient selection criteria, and standardizing outcome measures - are critically examined.