Trends Mol Med
· 2025 Aug · PMID 40533273
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Age-related clonal hematopoiesis in the elderly is mediated by expansion of mutant pre-leukemic hematopoietic cells, but the mechanism remains unclear. Recently, Agarwal et al. found elderly individuals exhibit the gut m...Age-related clonal hematopoiesis in the elderly is mediated by expansion of mutant pre-leukemic hematopoietic cells, but the mechanism remains unclear. Recently, Agarwal et al. found elderly individuals exhibit the gut microbial dysbiosis with enriched Gram-negative bacteria that release ADP-heptose into systemic circulation, which promotes pre-leukemic cell expansion through ALPK1-dependent signaling.
Trends Mol Med
· 2025 Dec · PMID 40527636
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Toll-like receptors (TLRs) play a pivotal role in both innate and adaptive immunity, primarily by detecting pathogen-associated molecular patterns (PAMPs) and orchestrating immune responses. Although TLR-driven activatio...Toll-like receptors (TLRs) play a pivotal role in both innate and adaptive immunity, primarily by detecting pathogen-associated molecular patterns (PAMPs) and orchestrating immune responses. Although TLR-driven activation of dendritic cells (DCs) and subsequent T cell differentiation are well characterized, the function of TLRs in B cells remains underexplored. In the context of obesity, excessive adipose tissue accumulation triggers chronic inflammation driven in part by activation of TLR signaling. This review explores the expression, function, and signaling mechanisms of TLRs in B cells, and emphasizes their role in modulating immune responses associated with obesity. Furthermore, we discuss how TLR-mediated inflammatory activity in B cells may contribute to metabolic dysregulation, and offer insights into the crosstalk between immune function and metabolic disease in obesity.
Trends Mol Med
· 2026 Jan · PMID 40527635
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Dysregulation of protein homeostasis contributes to many human diseases and is an emerging therapeutic target. Proteasome-mediated degradation requires ubiquitin tagging, a process regulated by E3 ligases and reversed by...Dysregulation of protein homeostasis contributes to many human diseases and is an emerging therapeutic target. Proteasome-mediated degradation requires ubiquitin tagging, a process regulated by E3 ligases and reversed by deubiquitinases (DUBs). Among DUBs, the ovarian tumor protease (OTU) family exhibits poly-ubiquitin linkage-specific activity and regulates diverse cellular processes. OTU dysregulation has been linked to diseases such as cancer, highlighting their potential as drug targets. This review summarizes current knowledge of OTU functions, regulatory mechanisms, and disease associations, as well as therapeutic strategies targeting OTUs. By examining these aspects, we aim to provide insights into the pathophysiological roles of OTUs and support ongoing efforts to develop OTU-targeted therapies for human diseases.
Trends Mol Med
· 2026 Jan · PMID 40527634
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The initiation of labour in humans remains poorly understood, although there is mounting evidence for a role for decidual macrophages. These may trigger labour by promoting a proinflammatory state, thereby modulating pro...The initiation of labour in humans remains poorly understood, although there is mounting evidence for a role for decidual macrophages. These may trigger labour by promoting a proinflammatory state, thereby modulating progesterone signalling and weakening fetal membranes. Preclinical work targeting macrophages therapeutically shows promise in preventing preterm labour, underscoring their significance in this process.
Dorigatti I, Gaythorpe KAM, Cox VM
… +2 more, Windram FA, Cator L
Trends Mol Med
· 2025 Oct · PMID 40527633
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The transmission potential of arboviruses is extremely sensitive to environmental conditions. This sensitivity is due to both their intimate relationship with ectothermic vectors and, in many cases, also to the involveme...The transmission potential of arboviruses is extremely sensitive to environmental conditions. This sensitivity is due to both their intimate relationship with ectothermic vectors and, in many cases, also to the involvement of multiple host species in zoonotic transmission cycles. Here, we review how climate change will alter the transmission ecology and risk of these important infections. The challenge of predicting how climate change will impact these systems is daunting, but the need for tools to manage arbovirus risk under climate change is urgent and imperative. We argue that the development of climate-driven mechanistic models of disease transmission informed by empirical surveillance data is urgently needed to inform future responses and for generating the evidence that policy needs to tackle this global public health risk.
Trends Mol Med
· 2025 Aug · PMID 40500629
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Acute kidney injury (AKI), with high morbidity and mortality, stems from tubular injury, vascular damage, and inflammation. Although often overlooked, early fibroblast activation is critical for kidney repair, challengin...Acute kidney injury (AKI), with high morbidity and mortality, stems from tubular injury, vascular damage, and inflammation. Although often overlooked, early fibroblast activation is critical for kidney repair, challenging traditional associations of fibroblasts with fibrosis. Here, we summarize fibroblast origins, heterogeneity, functions, and therapeutics in preventing or mitigating AKI.
Korkmaz F, Gimenez-Roig J, Sultana F
… +22 more, Laurencin V, Sen F, Cullen L, Sims S, Pallapati A, Rojekar S, Burganova G, Pevnev G, Cheliadinova U, Vasilyeva D, Moldavski O, Frolinger T, Gumerova A, Barak O, Ryu V, Lizneva D, Ye K, Schafer A, Rosen CJ, Yuen T, Kim SM, Zaidi M
Trends Mol Med
· 2025 Nov · PMID 40480851
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Follicle-stimulating hormone (FSH), traditionally known for regulating gonadal development, maturation, and estrogen secretion, has now been implicated in regulating fat and bone metabolism and cognition. Preclinical evi...Follicle-stimulating hormone (FSH), traditionally known for regulating gonadal development, maturation, and estrogen secretion, has now been implicated in regulating fat and bone metabolism and cognition. Preclinical evidence from genetic and pharmacological studies in rodent models, combined with human data from population-based observations, genetic studies, and a limited number of interventional trials, supports the notion of independent effects of FSH on the skeleton, fat, and brain. This evolving understanding of the nonreproductive roles of FSH presents potential therapeutic opportunities to mitigate age-related health challenges, which include osteoporosis, obesity, cardiovascular risk, and dementia. This review summarizes the current knowledge on the interplay between pituitary-derived FSH and peripheral and central tissues, as well as recent progress in therapeutic development.
Trends Mol Med
· 2025 Nov · PMID 40467364
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Endothelial-to-mesenchymal transition (EndMT) represents a dynamic process during which endothelial cells (ECs) loosen intercellular interactions, break down the basement membrane and undergo alterations in cell polarity...Endothelial-to-mesenchymal transition (EndMT) represents a dynamic process during which endothelial cells (ECs) loosen intercellular interactions, break down the basement membrane and undergo alterations in cell polarity to attain a mesenchymal phenotype. The intermediate stage of EndMT, known as partial EndMT, enables cells to exhibit partial functions and characteristics of both ECs and mesenchymal cells. This endows ECs with a unique physiological function and reflects the potential for reversing the EndMT process. In this article, we review the role of EndMT in diverse organs, the molecular network associated with EndMT, the occurrence of EndMT in cardiac physiological activities and pathophysiological damage, as well as the modulators of EndMT to offer novel perspectives for regulating EndMT-related physiological changes and disease progression.
Neuropsychiatric complications of cancer cachexia include apathy. Zhu et al. identified a brain circuit sensitive to tumor-driven interleukin-6 (IL-6) signaling that directly reduces motivation by suppressing dopaminergi...Neuropsychiatric complications of cancer cachexia include apathy. Zhu et al. identified a brain circuit sensitive to tumor-driven interleukin-6 (IL-6) signaling that directly reduces motivation by suppressing dopaminergic activity. Targeted circuit-based and pharmacologic interventions, including systemic anti-IL-6 antibodies, reversed motivational deficits and point to new therapeutic avenues for apathy.
Trends Mol Med
· 2025 Nov · PMID 40413101
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Acute lymphoblastic leukemia (ALL) is a rare disease in adults, but is the most common pediatric malignancy and the leading cause of death among children with cancer worldwide. While initial treatment regimens induce rem...Acute lymphoblastic leukemia (ALL) is a rare disease in adults, but is the most common pediatric malignancy and the leading cause of death among children with cancer worldwide. While initial treatment regimens induce remission in most patients, relapses still occur in many cases during or after treatment. Relapses are difficult to treat and continue to be one of the leading causes of ALL-related deaths. Thus, it is essential to understand the biological mechanisms underlying ALL relapses, and to identify reliable biomarkers for better relapse risk prediction and novel druggable targets for precision treatments tailored to risk profiles. Here we review the latest developments in ALL research with a focus on relapse mechanisms, and we discuss related hopes and challenges.
Verhezen T, Wouters A, Smits E
… +1 more, De Waele J
Trends Mol Med
· 2026 Jan · PMID 40393875
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Natural killer (NK) cells are innate lymphocytes that are crucial for eliminating malignant and infected cells, and have significant therapeutic potential against cancer and viral infections. However, their functionality...Natural killer (NK) cells are innate lymphocytes that are crucial for eliminating malignant and infected cells, and have significant therapeutic potential against cancer and viral infections. However, their functionality is often impaired under pathological conditions. Emerging evidence identifies mitochondria as key regulators of NK cell metabolism, fitness, and fate. This review examines how mitochondrial dysfunction impacts on NK cell activity in cancer, viral infections, and inflammatory disorders. We discuss strategies to target mitochondrial architecture, dynamics, and function as potential therapies to restore NK cell fitness. Finally, we highlight unanswered questions and future directions to better understand mitochondrial regulation in NK cells and its implications for therapeutic development.
Recent evidence underscores a reciprocal relationship between the gut microbiota and prostate cancer (PCa). Dysbiosis, often driven by Western dietary habits and antibiotic use, can heighten systemic inflammation and hin...Recent evidence underscores a reciprocal relationship between the gut microbiota and prostate cancer (PCa). Dysbiosis, often driven by Western dietary habits and antibiotic use, can heighten systemic inflammation and hinder antitumor immunity, thereby fostering PCa onset and progression. Conversely, certain gut microbes and their metabolites may protect against tumor growth by modulating immune and hormonal pathways that impact therapeutic responses, including androgen deprivation therapy (ADT). Emerging evidence links gut microbial shifts to PCa aggressiveness, potentially sustaining local androgen production and promoting resistance. In this review, we explore current understanding of the gut-PCa interplay, highlighting key knowledge gaps and the need for further research to clarify how targeting the microbiome might influence PCa outcomes.
Li B, Li B, Qiao X
… +6 more, Meng W, Xie Y, Gong J, Fan Y, Zhao Z, Li L
Trends Mol Med
· 2025 Oct · PMID 40335384
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Despite the primary impression of mitochondria as energy factories, these organelles are increasingly recognized for their multifaceted roles beyond energy production. Intriguingly, mitochondria can transfer between cell...Despite the primary impression of mitochondria as energy factories, these organelles are increasingly recognized for their multifaceted roles beyond energy production. Intriguingly, mitochondria can transfer between cells, influencing physiological and pathological processes through intercellular trafficking termed 'mitochondrial transfer.' This phenomenon is important in maintaining metabolic homeostasis, enhancing tissue regeneration, exacerbating cancer progression, and facilitating immune modulation, depending on the cell type and microenvironment. Recently, mitochondrial transfer has emerged as a promising therapeutic target for tissue repair and antitumor therapy. Here, we summarize and critically review recent advances in this field. We aim to provide an updated overview of the mechanisms and potential therapeutic avenues associated with mitochondrial transfer in various diseases from the perspective of different donor cells.
Pyroptosis is a type of programmed inflammatory cell death characterized by balloon-like swelling, membrane rupture, and the release of inflammatory cytokines and danger signals. Pyroptosis is directly triggered by activ...Pyroptosis is a type of programmed inflammatory cell death characterized by balloon-like swelling, membrane rupture, and the release of inflammatory cytokines and danger signals. Pyroptosis is directly triggered by activated gasdermins (GSDMs) which bind to membrane phospholipids, oligomerize, and form pores in cell membranes. GSDM activation is mediated by various effector proteases via cleavage of the linker region or post-translational modification to release the active N-terminal fragment in response to a variety of pathogenic or intrinsic danger signals. GSDM-mediated pyroptosis is involved in the pathogenesis of an array of infectious and inflammatory diseases and cancers. This review discusses recent advances related to the physiological and pathological functions of GSDM-mediated pyroptosis, as well as therapeutic strategies targeting pyroptosis.
Trends Mol Med
· 2025 Oct · PMID 40307075
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Mesothelial cells (MCs) constitute a dynamic mesothelium in which their numerous crucial functions synergistically interact with other cells to maintain serosal integrity and homeostasis. Previous studies have confirmed...Mesothelial cells (MCs) constitute a dynamic mesothelium in which their numerous crucial functions synergistically interact with other cells to maintain serosal integrity and homeostasis. Previous studies have confirmed the crucial role of interactions between MCs and tumor cells in tumorigenesis and progression in the tumor microenvironment (TME). However, recent research has found that MCs can induce an immunosuppressive microenvironment by secreting various cytokines, chemokines, and exosomes which recruit immunosuppressive cells or interact with immune cells, thus contributing to tumor progression. This review primarily examines the immunoregulatory role of MCs in the TME of mesothelioma and metastatic pleural and peritoneal carcinomas. It also explores the potential mechanisms by which these interactions induce immunosuppression and their impact on tumor growth and therapy.
Thangavelu PU, Lin CY, Forouz F
… +3 more, Tanaka K, Dray E, Duijf PHG
Trends Mol Med
· 2025 Dec · PMID 40300971
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Genomic instability is a hallmark of cancer. It fuels cancer progression and therapy resistance. As 'the guardian of the genome', the tumor suppressor protein p53 protects against genomic damage. Canonically, the retinob...Genomic instability is a hallmark of cancer. It fuels cancer progression and therapy resistance. As 'the guardian of the genome', the tumor suppressor protein p53 protects against genomic damage. Canonically, the retinoblastoma protein (RB) is 'the sentry of cell cycle entry', as it dictates whether a cell enters the cell cycle to divide. However, the RB pathway also controls myriad non-canonical cellular processes, including metabolism, stemness, angiogenesis, apoptosis, and immune surveillance. We discuss how frequent RB pathway inactivation and underlying mechanisms in cancers affect these processes. We focus on RB's - rather than p53's - 'guardian of the genome' functions in DNA replication, DNA repair, centrosome duplication, chromosome segregation, and chromatin organization. Finally, we review therapeutic strategies, challenges, and opportunities for targeting RB pathway alterations in cancer.
Verdys P, Johansen AZ, Gupta A
… +5 more, Presti M, Dionisio E, Madsen DH, Curioni-Fontecedro A, Donia M
Trends Mol Med
· 2025 Nov · PMID 40274520
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Acquired resistance to immunotherapy (ARI) is a major challenge in solid tumors, limiting long-term success in up to 65% of patients who initially respond to immunotherapy. Defining ARI clinically remains complex, but on...Acquired resistance to immunotherapy (ARI) is a major challenge in solid tumors, limiting long-term success in up to 65% of patients who initially respond to immunotherapy. Defining ARI clinically remains complex, but ongoing efforts aim to establish standardized criteria. This review describes recent insights into ARI, revealing complex mechanisms involving both tumor-intrinsic mechanisms - such as antigen loss and presentation defects, interferon γ (IFNγ) insensitivity, tumor-mediated T cell exclusion, and metabolic reprogramming - as well as extrinsic factors such as inhibitory molecule upregulation, immunosuppressive cells, extracellular matrix (ECM) remodeling, and dysbiotic microbiota. Understanding the development of ARI is crucial for prevention and effective interventions. The integration of innovative strategies and translational research on appropriately collected samples is key to overcoming ARI and ensuring durable benefits for patients.