Trends Mol Med
· 2026 Feb · PMID 41444102
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Palma et al. show that melanoma cells adapt to oxidative stress imposed by the lymphatic niche by shifting their dependency from glutathione peroxidase 4 (GPX4) to ferroptosis suppressor protein 1 (FSP1), to protect from...Palma et al. show that melanoma cells adapt to oxidative stress imposed by the lymphatic niche by shifting their dependency from glutathione peroxidase 4 (GPX4) to ferroptosis suppressor protein 1 (FSP1), to protect from ferroptosis. This highlights the importance of the microenvironment in shaping ferroptosis defenses and supports FSP1 as a targetable vulnerability for lymph node metastases.
Santiago JA, Gutierrez-Silva JC, Hsu WC
… +5 more, Sanchez K, Almanza C, Ramos W, Haq IU, Rundek T
Trends Mol Med
· 2025 Dec · PMID 41444101
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Glucagon-like peptide-1 receptor agonists (GLP1-RAs), widely used for type 2 diabetes mellitus, are emerging as promising neuroprotective therapies in Alzheimer's disease (AD) and Parkinson's disease (PD). Agents such as...Glucagon-like peptide-1 receptor agonists (GLP1-RAs), widely used for type 2 diabetes mellitus, are emerging as promising neuroprotective therapies in Alzheimer's disease (AD) and Parkinson's disease (PD). Agents such as exenatide, lixisenatide, and liraglutide have demonstrated disease-modifying potential in preclinical and clinical studies. However, translation remains hindered by the absence of validated biomarkers to guide patient selection, track target engagement, and monitor progression. Here, we review the mechanistic links between GLP1-RA signaling and neurodegeneration, summarize the evolving clinical evidence, and highlight emerging blood-based and molecular biomarkers, including those tied to insulin signaling, neurodegeneration, and metabolic and cardiovascular dysfunction, that may accelerate therapeutic development. Integrating these biomarkers with digital phenotyping and artificial intelligence could enable precision approaches to advance GLP1-RA research and clinical use in neurodegeneration.
Trends Mol Med
· 2026 May · PMID 41437405
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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...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.
Okugbeni N, Cole V, Kroon E
… +3 more, Sargeant TJ, Loos B, Kinnear C
Trends Mol Med
· 2025 Dec · PMID 41419360
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Tuberculosis (TB) remains a major global health burden, prompting heightened efforts towards host-directed therapies (HDT). Autophagy, a key antimicrobial and immunomodulatory process, is a promising candidate for HDT. H...Tuberculosis (TB) remains a major global health burden, prompting heightened efforts towards host-directed therapies (HDT). Autophagy, a key antimicrobial and immunomodulatory process, is a promising candidate for HDT. However, despite encouraging preclinical results, autophagy-targeting strategies have shown limited clinical success, in part due to the lack of accurate profiling of patient-derived autophagy flux across the TB spectrum. This gap limits our understanding of baseline autophagy dynamics and hinders the rational design of HDT. This review highlights patient-derived autophagic flux as a dynamic, quantitative readout of autophagy activity and an underutilized element in TB biomarker and therapeutic research. We examine autophagy flux assessment methodologies and propose its role as a biomarker for TB diagnosis, prognosis, and patient stratification in personalized HDT strategies.
Zhao L, Zheng R, Liu W
… +5 more, Li X, Liu H, Yin H, Zhang R, Yang A
Trends Mol Med
· 2025 Dec · PMID 41372079
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Immunotherapy resistance, orchestrated largely by the tumor microenvironment, remains a major clinical challenge. Recent advances highlight metabolic reprogramming as a key driver of this resistance. In this review we fo...Immunotherapy resistance, orchestrated largely by the tumor microenvironment, remains a major clinical challenge. Recent advances highlight metabolic reprogramming as a key driver of this resistance. In this review we focus on cholesterol metabolism, a central hub that profoundly reshapes the tumor immune landscape. We dissect how dysregulated cholesterol pathways fortify tumor cells against immune attack while simultaneously suppressing effector immune cells. We conceptualize cholesterol metabolism as a critical metabolic-immune checkpoint, a novel framework for understanding this tumor-immune crosstalk. Finally, we comprehensively review emerging therapeutic strategies targeting this checkpoint, illuminating a promising translational path to dismantle metabolic barriers and overcome immunotherapy resistance.
Chaliha DR, Lam V, Sharif A
… +4 more, Redwood E, Vaccarezza M, Takechi R, Mamo JCL
Trends Mol Med
· 2026 Jun · PMID 41365701
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In this opinion, we propose that compromised microvascular perfusion and inflammation are fundamental drivers of chronic pain syndromes, with many of these conditions sharing a common etiology involving suboptimal blood...In this opinion, we propose that compromised microvascular perfusion and inflammation are fundamental drivers of chronic pain syndromes, with many of these conditions sharing a common etiology involving suboptimal blood flow and inflammatory cascades. This hypothesis links capillary constriction, hypoxia, inflammation, and nociceptor activation into a unified framework for understanding pain mechanisms. For each example syndrome, we explore specific nuances, molecular mechanisms, and therapeutic opportunities, focusing on the interplay between hypoxia and inflammation. Current treatments often emphasize anti-angiogenic or broad-spectrum approaches, which may neglect the microvascular and hypoxic origins. We review studies investigating microvascular hypoperfusion and inflammation in pain and suggest that targeted therapies addressing vascular deficits and inflammatory responses could better disrupt the hypoxia-inflammation cycle, offering novel avenues for treatment.
Trends Mol Med
· 2026 Jun · PMID 41354600
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To date, research on premature ovarian insufficiency (POI) primarily centers on ovarian dysfunction and systemic hormonal imbalances, with limited attention given to associated endometrial alterations. Given the critical...To date, research on premature ovarian insufficiency (POI) primarily centers on ovarian dysfunction and systemic hormonal imbalances, with limited attention given to associated endometrial alterations. Given the critical role of the endometrium in reproductive function and its potential contribution to POI-related infertility, in this review, we bridge the knowledge gap regarding endometrial aspects of POI. We discuss the physiology and pathophysiology alterations in the POI endometrium, the multilevel endometrial changes spanning histological architecture, molecular signatures, and functional capacity, and clinical ramifications for fertility potential. In addition, we critically evaluate both established and novel therapeutic interventions targeting these endometrial abnormalities, paying particular attention to their potential to restore reproductive function.
Trends Mol Med
· 2026 Jun · PMID 41330858
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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...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.
Petrică M, Ferreira-Marques M, Ribeiro RFN
… +1 more, Cavadas C
Trends Mol Med
· 2026 Jun · PMID 41330857
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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...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.
Ribaldone DG, Valdiserra G, Di Salvo C
… +3 more, Puxeddu I, Bertani L, Antonioli L
Trends Mol Med
· 2025 Nov · PMID 41314864
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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 reflec...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.
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 multi...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.
Trends Mol Med
· 2026 Jun · PMID 41266190
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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 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.
Trends Mol Med
· 2026 Jun · PMID 41260953
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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. Conventi...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.
Trends Mol Med
· 2026 May · PMID 41233253
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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...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 discr...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.
Trends Mol Med
· 2026 Jan · PMID 41176492
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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 su...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.
Trends Mol Med
· 2026 Apr · PMID 41168024
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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/...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.