Trends Mol Med
· 2026 Mar · PMID 41881707
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Mechanical forces regulate development, homeostasis, and repair in the skin, lung, and cornea-external barrier organs that are exposed to stretch, shear, and stiffness. Dysregulated mechanotransduction drives fibrosis, i...Mechanical forces regulate development, homeostasis, and repair in the skin, lung, and cornea-external barrier organs that are exposed to stretch, shear, and stiffness. Dysregulated mechanotransduction drives fibrosis, inflammation, and impaired repair via conserved pathways [Piezo1 (Piezo-type mechanosensitive ion channel 1), TRPV4 (transient receptor potential vanilloid 4), and integrin-YAP (Yes-associated protein)]. Targeting these circuits with small molecules, biologics, or stiffness-tuned biomaterials offers a novel category of cross-organ therapies. As mechanosensitive pathways and mechanically informed biomaterials advance toward clinical testing, an integrated cross-organ perspective is urgently needed to address unmet therapeutic needs in chronic barrier diseases. This review unifies disparate insights into biophysics, molecular biology, and clinical practice to reveal how shared mechanisms underpin barrier pathologies and enable breakthrough mechanomedicine treatments.
Shang E, Aftab O, Dayanamby A
… +1 more, Greaves LC
Trends Mol Med
· 2026 Mar · PMID 41881706
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Mitochondria, once viewed mainly as cellular powerhouses, are now recognised as key regulators of cancer metabolism, redox balance, and immune interactions. While early models emphasised a switch to aerobic glycolysis, m...Mitochondria, once viewed mainly as cellular powerhouses, are now recognised as key regulators of cancer metabolism, redox balance, and immune interactions. While early models emphasised a switch to aerobic glycolysis, many tumours exhibit metabolic plasticity and retain oxidative phosphorylation capacity. Mitochondrial DNA (mtDNA) mutations are common across cancers, yet their roles in carcinogenesis and therapy response remain unclear. Emerging base-editing technologies now enable modelling of these mutations, allowing the exploration of their impact on tumourigenesis, which may differ depending on mutation type, heteroplasmy, and tissue origin. mtDNA alterations also shape immune responses within the tumour microenvironment and therefore may influence treatment sensitivity. This review integrates recent advances on mtDNA's role in cancer biology and explores therapeutic opportunities for targeting mitochondrial metabolism.
Wouda SHT, Geertsema S, van Goor H
… +3 more, Dijkstra G, Faber KN, Bourgonje AR
Trends Mol Med
· 2026 Mar · PMID 41876321
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An intact gut barrier is crucial to human health. Functional assessment of gut barrier function and permeability in humans is laborious and demanding. Blood-based biomarkers that reflect gut barrier integrity have gained...An intact gut barrier is crucial to human health. Functional assessment of gut barrier function and permeability in humans is laborious and demanding. Blood-based biomarkers that reflect gut barrier integrity have gained increasing attention for their potential role in monitoring gut barrier impairments across various conditions. Several candidate biomarkers-including intestinal fatty acid-binding protein, citrulline, zonulin, lipopolysaccharide-binding protein, and soluble CD14-reflect epithelial damage, microbial translocation, or tight junction dysfunction. This review highlights novel technologies for quantifying blood-based biomarkers to assess gut barrier function across diseases. Furthermore, it emphasizes the value of integrating complementary blood-based biomarkers across different populations to improve disease monitoring and the development of targeted therapies.
Trends Mol Med
· 2026 Mar · PMID 41864757
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Whether endometriosis is a progressive disease remains debated. Central to this debate is understanding the natural history of endometriotic lesions, which are essentially wounds undergoing repeated tissue injury and rep...Whether endometriosis is a progressive disease remains debated. Central to this debate is understanding the natural history of endometriotic lesions, which are essentially wounds undergoing repeated tissue injury and repair. Viewing the disease through this lens, we reassess the literature on the progression, or absence thereof, of endometriosis and offer our perspective on this debate by delineating the aggravating and mitigating factors that influence lesional progression. We propose that the degree of lesional fibrosis, measurable via elastography as lesional stiffness, represents a promising marker for progression, as it correlates with aberrant histology, molecular alterations, symptom severity, clinical prognosis, and lesional mechanobiology. Lesional stiffness could aid in diagnosis, guide treatment choice, and predict outcomes, providing a valuable tool for managing endometriosis.
Trends Mol Med
· 2026 Mar · PMID 41864756
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Aging, once viewed as an irreversible process, is now considered a modifiable process. Recent advances in cellular reprogramming reveal that transient expression of reprogramming factors can reverse molecular hallmarks o...Aging, once viewed as an irreversible process, is now considered a modifiable process. Recent advances in cellular reprogramming reveal that transient expression of reprogramming factors can reverse molecular hallmarks of aging while preserving somatic cell identity. This 'partial reprogramming' rejuvenates tissues, restores regenerative capacity, and, in some models, extends lifespan without the tumorigenic risks of full dedifferentiation. In this review, we summarize genetic and chemical strategies for partial reprogramming, discuss their tissue-specific effects in vivo, and evaluate their implications for tissue regeneration and age-related disease. We further examine key challenges for clinical translation, including safety, delivery strategies, and temporal control of reprogramming.
Trends Mol Med
· 2026 Jun · PMID 41862402
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Therapy-resistant cancers exploit cellular stress programs to survive. Evidence from neuroendocrine prostate cancer reveals that the loss of nitric oxide-dependent redox signaling amplifies endoplasmic reticulum stress a...Therapy-resistant cancers exploit cellular stress programs to survive. Evidence from neuroendocrine prostate cancer reveals that the loss of nitric oxide-dependent redox signaling amplifies endoplasmic reticulum stress and lineage plasticity. Restoring physiological nitroso-redox balance may reprogram stress adaptation and expose new vulnerabilities in aggressive cancers.
Mutalik VK, Inman JL, Chang H
… +2 more, Arkin A, Mao JH
Trends Mol Med
· 2026 Mar · PMID 41862401
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Bacteriophages (phages) are emerging as programmable biological therapeutics in oncology, extending beyond their traditional antimicrobial applications. This review proposes a phage-microbiome-immune-oncology axis that l...Bacteriophages (phages) are emerging as programmable biological therapeutics in oncology, extending beyond their traditional antimicrobial applications. This review proposes a phage-microbiome-immune-oncology axis that links microbial dynamics, immune modulation, and engineered phages to guide precision cancer prevention and therapy. Phages can eliminate cancer-associated bacteria, remodel the tumor microenvironment, enhance antitumor immunity, and deliver targeted therapeutic payloads. However, several critical challenges must be addressed to realize this therapeutic potential, particularly host immune responses that limit repeat dosing, inefficient tumor penetration, and the need for rigorous clinical validation. By examining phage-host-tumor interactions through robust model systems and highlighting translational opportunities, this review establishes phage therapy as a promising frontier in precision oncology that warrants accelerated clinical development.
Trends Mol Med
· 2026 Mar · PMID 41856868
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The placenta is an essential organ that supports fetal development during pregnancy. The establishment of human trophoblast stem cells has enhanced our understanding of placental development; however, their limited diver...The placenta is an essential organ that supports fetal development during pregnancy. The establishment of human trophoblast stem cells has enhanced our understanding of placental development; however, their limited diversity constrains our ability to capture interindividual variation. Patient-specific trophoblast stem cells (pTSCs), derived from induced pluripotent stem cells, fibroblasts, cytotrophoblasts, or chorionic villus tissue, retain the unique genetic and epigenetic backgrounds of individual patients. Notably, chorionic villus-derived trophoblast stem cells can be obtained without terminating a pregnancy, allowing for integration with prospective clinical data. pTSCs, therefore, provide powerful platforms to investigate the pathogenesis of placental disorders, assess individual risk, and advance personalized therapeutic strategies. This review highlights recent advances in pTSC derivation and discusses their potential applications.
Zhu Z, Mathew J, Barrett B
… +5 more, Wang HH, Huff AL, Armstrong TD, Jaffee EM, Zaidi N
Trends Mol Med
· 2026 Mar · PMID 41832055
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Intercepting cancer development with immune-modulating approaches before cancer has established is an emerging and promising strategy to reduce the global cancer burden. By safely harnessing the immune system, cancer vac...Intercepting cancer development with immune-modulating approaches before cancer has established is an emerging and promising strategy to reduce the global cancer burden. By safely harnessing the immune system, cancer vaccines can enhance immune surveillance and lead to the elimination of transforming cells at the earliest stages of carcinogenesis, particularly when the immune microenvironment is least hostile and the potential for cure is greatest. In this review, we discuss the fundamental rationale behind immuno-interception strategies, provide an overview of advances in cancer interception clinical trials, and highlight key considerations and future directions for achieving effective cancer interception.
A recent study by Angelino et al. uncovered an intracellular signaling pathway involved in musculoskeletal mitochondrial dysfunction in cancer cachexia. Both humans and mice with cancer cachexia display impaired 3',5'-cy...A recent study by Angelino et al. uncovered an intracellular signaling pathway involved in musculoskeletal mitochondrial dysfunction in cancer cachexia. Both humans and mice with cancer cachexia display impaired 3',5'-cyclic adenosine monophosphate (cAMP)-protein kinase A-cAMP response element-binding protein 1 signaling, which leads to mitochondrial dysfunction. By rescuing this pathway with a phosphodiesterase-4 inhibitor, the authors highlight a potential therapeutic strategy for cancer cachexia.
Trends Mol Med
· 2026 Mar · PMID 41826143
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Ferroptosis, a regulated form of cell death, is determined by iron-dependent lipid peroxidation. A selenoenzyme called glutathione peroxidase 4 (GPX4) detoxifies phospholipid hydroperoxides at the heart of this process....Ferroptosis, a regulated form of cell death, is determined by iron-dependent lipid peroxidation. A selenoenzyme called glutathione peroxidase 4 (GPX4) detoxifies phospholipid hydroperoxides at the heart of this process. As the pivotal gatekeeper of ferroptosis, GPX4 is implicated in a wide range of pathologies, including cancer, neurodegeneration, acute renal failure, and infection. In this review, we discuss how GPX4 transcription and mRNA stability are controlled by transcription factors, epigenetic modifications, and noncoding RNAs and how GPX4 degradation and activity are modulated by post-translational modifications, including ubiquitination, phosphorylation, palmitoylation, methylation, hydroxylation, and lactylation. We also summarize new therapeutic methods targeting GPX4, namely the ferroptosis inducers for cancer therapy and ferroptosis inhibitors that prevent ferroptosis-related damage.
Trends Mol Med
· 2026 Mar · PMID 41781250
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A groundbreaking study by Yue et al. reveals adenosine signaling as the convergent mechanism underlying the rapid antidepressant effects of both ketamine and electroconvulsive therapy. This discovery not only resolves a...A groundbreaking study by Yue et al. reveals adenosine signaling as the convergent mechanism underlying the rapid antidepressant effects of both ketamine and electroconvulsive therapy. This discovery not only resolves a longstanding mechanistic puzzle but also opens new therapeutic avenues, including novel ketamine derivatives and nonpharmacological interventions that harness adenosine's antidepressant potential.
Trends Mol Med
· 2026 Mar · PMID 41781249
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Cachexia and hypercalcemia frequently complicate advanced renal cancer. A recent Nature Medicine study by Abu-Remaileh et al. shows that pharmacologic hypoxia-inducible factor 2 (HIF2) inhibition rapidly suppresses parat...Cachexia and hypercalcemia frequently complicate advanced renal cancer. A recent Nature Medicine study by Abu-Remaileh et al. shows that pharmacologic hypoxia-inducible factor 2 (HIF2) inhibition rapidly suppresses parathyroid hormone-related protein (PTHrP), reverses metabolic wasting, and normalizes calcium levels, redefining these paraneoplastic syndromes as targetable endocrine disorders rather than secondary consequences of tumor burden.
Trends Mol Med
· 2026 Feb · PMID 41760516
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In recent years, numerous studies have highlighted the crucial role of mitochondrial metabolism in cancer progression. This sparked interest in its potential as a target for cancer therapy and prompted the clinical evalu...In recent years, numerous studies have highlighted the crucial role of mitochondrial metabolism in cancer progression. This sparked interest in its potential as a target for cancer therapy and prompted the clinical evaluation of multiple drugs targeting mitochondrial metabolism. Regrettably, most have showed limited efficacy and safety, raising concerns about the viability of mitochondrial inhibitors in cancer treatment. However, emerging evidence suggests that shifting the focus away from mitochondrial bioenergetics and targeting other aspects of mitochondrial biology, may have a meaningful impact on cancer progression with milder side effects. In this review, we discuss emerging actionable targets and strategies to tailor the administration of inhibitors of mitochondrial pathways for cancer therapy.
Trends Mol Med
· 2026 Mar · PMID 41690900
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Huntington's disease (HD) is usually described as rare, tragic, and intractable. Yet, HD offers a strategically unique entry point for neuroscience. With its genetic clarity, relatively predictable course, and organized...Huntington's disease (HD) is usually described as rare, tragic, and intractable. Yet, HD offers a strategically unique entry point for neuroscience. With its genetic clarity, relatively predictable course, and organized global community, HD provides the clearest path to advancing brain repair.
Trends Mol Med
· 2026 Jan · PMID 41565506
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A growing number of diseases are now treated with immunotherapies, which consist of interventions that suppress or stimulate the patient's immune system. Because individual humans express a unique repertoire of adaptive...A growing number of diseases are now treated with immunotherapies, which consist of interventions that suppress or stimulate the patient's immune system. Because individual humans express a unique repertoire of adaptive immune receptors, the efficacy of immunotherapies typically varies from person to person. Next generation sequencing of adaptive immune receptor repertoires, combined with machine learning or statistical analysis, has emerged as a sensitive means of stratifying patients based on their immune status, particularly in the fields of cancer and autoimmune disease therapy. The sensitivity and specificity of these approaches rely heavily on the methods of deriving features from each individual repertoire. Here, we review recent trends in stratification methods and highlight their limitations, including the need for data standardization and sharing.
Trends Mol Med
· 2026 Jan · PMID 41545236
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Single cell RNA sequencing (scRNA-seq) has revolutionized the field of biology and become the most powerful tool for evaluating transcriptional profiles of a biological sample. Given its power, it is widely utilized acro...Single cell RNA sequencing (scRNA-seq) has revolutionized the field of biology and become the most powerful tool for evaluating transcriptional profiles of a biological sample. Given its power, it is widely utilized across multiple disciplines, including chimeric antigen receptor (CAR)-T cell therapy. In this review, we provide a comprehensive summary of published studies that have used scRNA-seq to analyze clinical CAR-T cells, focusing on T cell exhaustion, cytotoxicity, memory, expansion, clonal diversity, and cytokines. We also highlight findings on activation, CD4+/CD8+ ratios, proliferation, regulatory T cells (Tregs) and metabolism, and their relevance to patient response across diseases. Finally, we discuss the limitations and future directions of scRNA-seq in CAR-T cell research, providing key insights for clinicians and researchers.
Fuster-Martínez I, Bernal-Monterde V, Bidault G
… +2 more, Arbonés-Mainar JM, Vidal-Puig A
Trends Mol Med
· 2026 Jan · PMID 41545235
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The liver has a unique microarchitecture, with hepatic sinusoids receiving blood from the portal vein and hepatic artery and draining into the central vein. This flow establishes an oxygen gradient along the sinusoids cr...The liver has a unique microarchitecture, with hepatic sinusoids receiving blood from the portal vein and hepatic artery and draining into the central vein. This flow establishes an oxygen gradient along the sinusoids critical for defining the liver zonation. In metabolic dysfunction-associated steatotic liver disease (MASLD), fat accumulation and fibrosis disrupt this architecture, contributing to localised hypoxia. Mounting evidence implicates hypoxia in MASLD, including the activation of canonical hypoxia sensors such as hypoxia-inducible factors. Moreover, chronic intermittent hypoxia, characteristic of obstructive sleep apnoea (OSA), is epidemiologically and mechanistically associated with MASLD progression. This review examines the intrahepatic oxygen dynamics, the interplay between OSA and MASLD, and molecular responses to hypoxia, proposing intrahepatic hypoxia as a spatial determinant of liver injury.