Trends in Molecular Medicine

Microvascular hypoxia and inflammation in chronic pain syndromes 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.

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Cholesterol metabolism: a new checkpoint in cancer immunity Immunotherapy resistance, orchestrated largely by the tumor microenvironment (TME), 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.

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Microvascular hypoxia and inflammation in chronic pain syndromes 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.

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The overlooked uterine factor: unlocking endometrium potential in premature ovarian insufficiency 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.

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The overlooked uterine factor: unlocking endometrium potential in premature ovarian insufficiency 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.

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Repurposing of microbial proteins as new-generation therapeutic agents for biomedical applications 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.

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Neuroendocrine timekeepers: changes in normal and premature aging 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.

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Repurposing of microbial proteins as new-generation therapeutic agents for biomedical applications 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.

ONLINE NOW: Repurposing of microbial proteins as new-generation therapeutic agents for biomedical applications

Neuroendocrine timekeepers: changes in normal and premature aging 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.

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Predicting healthspan and disease risks through biological age 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.

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The right drug at the right time: key to IBD success 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.

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Predicting healthspan and disease risks through biological age 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.

ONLINE NOW: Predicting healthspan and disease risks through biological age

The right drug at the right time: key to IBD success 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.

ONLINE NOW: The right drug at the right time: key to IBD success

Tryptophan metabolites at the service of neuroimmune sensing of microbes 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.

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Emerging innovative treatments for leptomeningeal metastatic tumors 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.

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Tryptophan metabolites at the service of neuroimmune sensing of microbes 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.

ONLINE NOW: Tryptophan metabolites at the service of neuroimmune sensing of microbes

Emerging innovative treatments for leptomeningeal metastatic tumors 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.

ONLINE NOW: Emerging innovative treatments for leptomeningeal metastatic tumors

Molecular advances and therapeutic potential in leveraging hepcidin 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.

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Androgen receptor and its coregulators in sex-biased diseases 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.

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Molecular advances and therapeutic potential in leveraging hepcidin 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.

ONLINE NOW: Molecular advances and therapeutic potential in leveraging hepcidin

Androgen receptor and its coregulators in sex-biased diseases 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.

ONLINE NOW: Androgen receptor and its coregulators in sex-biased diseases

The November issue of Trends in Molecular Medicine is now online! www.cell.com/trends/molec...

Special thanks to all the authors and reviewers for their contribution!

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Transcriptional landscape of skeletal muscle in cancer patients 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.

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Transcriptional landscape of skeletal muscle in cancer patients 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.

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ANGPTL3/8: one target, multiple lipid 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.

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ICYMI: ONLINE NOW: Precision medicine for sodium channelopathy-related autism and epilepsy

ANGPTL3/8: one target, multiple lipid 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.

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ONLINE NOW: Precision medicine for sodium channelopathy-related autism and epilepsy

The biology of congenital urinary bladder outflow obstruction 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.

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The biology of congenital urinary bladder outflow obstruction 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.

ONLINE NOW: The biology of congenital urinary bladder outflow obstruction