Trends Mol Med
· 2025 Oct · PMID 40268589
·
Publisher ↗
Soft-tissue fibroproliferative conditions (FPCs) affect many organs. All demonstrate the accumulation of (myo)fibroblasts and extracellular matrix. Currently, FPCs are classified according to the affected body site/organ...Soft-tissue fibroproliferative conditions (FPCs) affect many organs. All demonstrate the accumulation of (myo)fibroblasts and extracellular matrix. Currently, FPCs are classified according to the affected body site/organ. To promote research into the etiological mechanisms that drive pathological FPCs, we propose a new, more clinically grounded, FPC classification that is based on the intent and severity of the fibroproliferation. There are three categories: responsive, replacement, and reconstructive FPCs. Reconstructive FPCs (e.g., keloids) have quasi-neoplastic behaviors, including local invasiveness, and serve as a bridge between fibrosis and cancers. Comparisons of reconstructive FPCs to both cancers and the other FPC categories may help elucidate their pathogenic cellular properties, microenvironmental components, and intracellular-signaling mechanisms. Thus, the new FPC classification may promote research in the fibrosis field.
Berryhill BA, Gil-Gil T, Smith AP
… +1 more, Levin BR
Trends Mol Med
· 2025 Nov · PMID 40268588
·
Full text
Fueled by the increasing abundance of antibiotic-resistant pathogens, there has been a resurrection in the use of bacterial viruses (bacteriophages or 'phage') for therapeutic applications. Phage therapy was used in the...Fueled by the increasing abundance of antibiotic-resistant pathogens, there has been a resurrection in the use of bacterial viruses (bacteriophages or 'phage') for therapeutic applications. Phage therapy was used in the early 20th century to limited success, which we attribute to its haphazard employment. To avoid repeating the mistakes of the past, this Opinion first evaluates the historical reasons for the failure of phage therapy, analyzes the current state of the field, and ultimately makes recommendations for how to proceed with contemporary phage therapy. Despite many advances in phage biology, crucial gaps in our knowledge persist. Our recommendations require physicians, scientists, and public-policy leaders to cooperate to bridge the outstanding gaps around phage therapy to develop phage into a useful therapeutic tool.
Trends Mol Med
· 2025 Dec · PMID 40246604
·
Publisher ↗
Keratinocytes, the predominant cell type in the epidermis, are indispensable for maintaining skin barrier integrity, mediating host defense, and orchestrating immune responses. Beyond these well-established functions, em...Keratinocytes, the predominant cell type in the epidermis, are indispensable for maintaining skin barrier integrity, mediating host defense, and orchestrating immune responses. Beyond these well-established functions, emerging evidence reveals their dynamic interactions with the nervous system and their capacity to retain inflammatory memory. These discoveries position keratinocytes as key drivers of the onset, progression, and relapse of inflammatory skin diseases. In this review, we delve into the mechanisms underlying keratinocyte crosstalk with immune and neural cells, the metabolic reprogramming, including lactate and other metabolites, that may drive inflammatory memory, and the broader implications for disease pathogenesis and recurrence. Finally, we discuss the challenges to, and therapeutic potential of, targeting keratinocytes for the treatment of chronic inflammatory skin conditions.
Benedicto I, Hamczyk MR, Dorado B
… +1 more, Andrés V
Trends Mol Med
· 2026 Jan · PMID 40240194
·
Publisher ↗
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare genetic disease caused by progerin, a broadly expressed mutant variant of lamin A protein that accelerates aging and leads to premature death typically in adole...Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare genetic disease caused by progerin, a broadly expressed mutant variant of lamin A protein that accelerates aging and leads to premature death typically in adolescence. Progerin affects many organs and reproduces many characteristics of physiological aging, with the main cause of death in HGPS being atherosclerotic cardiovascular disease (CVD). Due to the rarity of HGPS, advances in understanding the disease and progress toward new therapeutic approaches are crucially dependent on preclinical models. We discuss recent research developments from a variety of HGPS experimental systems, with a special focus on in vivo studies of the role of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) that are key players in atherosclerosis.
Trends Mol Med
· 2025 Dec · PMID 40234116
·
Publisher ↗
Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple ne...Phosphoglycerate kinase 1 (PGK1) is a highly conserved enzyme that catalyzes the initial ATP-producing step in glycolysis. Improving cellular energy production by increasing PGK1 activity may be beneficial in multiple neurological conditions where cell metabolism is dysregulated, including Parkinson's disease (PD) and motor neuron disease (MND). This review examines recent evidence that suggests increasing PGK1 activity may be beneficial in multiple neurological conditions and discusses the current challenges surrounding the development of PGK1-focused therapies. PGK1 has considerable therapeutic potential, but novel PGK1 activators are needed to maximize the benefit for patients.
Trends Mol Med
· 2025 Oct · PMID 40199696
·
Full text
A combination of intracellular and extracellular abnormalities of the nervous system, coupled with inflammation and intestinal dysbiosis, form the hallmarks of neurodegenerative diseases (NDDs). While it is difficult to...A combination of intracellular and extracellular abnormalities of the nervous system, coupled with inflammation and intestinal dysbiosis, form the hallmarks of neurodegenerative diseases (NDDs). While it is difficult to identify the precise order in which these hallmarks manifest in NDDs because of their mutualistic nature, they cumulatively result in nervous or neuronal damage that characterizes neurodegeneration. In this review we discuss the roles of microRNAs (miRNAs) in the maintenance of nervous system homeostasis and their implication for NDDs. We further highlight recent advances in, and limitations of, miRNA therapeutics in NDDs and their future potential.
Trends Mol Med
· 2025 Jun · PMID 40185675
·
Publisher ↗
In a recent study in Cancer Discovery, Maciag et al. introduce BBO-8520, a novel inhibitor targeting both the active and inactive states of KRAS. This dual inhibition shows superior target engagement and prolonged tumor...In a recent study in Cancer Discovery, Maciag et al. introduce BBO-8520, a novel inhibitor targeting both the active and inactive states of KRAS. This dual inhibition shows superior target engagement and prolonged tumor suppression, offering a compelling strategy to overcome resistance development and improve outcomes in KRAS-mutant cancers.
Antigny F, Crottès D, Vandier C
… +2 more, Capuano V, Guéguinou M
Trends Mol Med
· 2025 Oct · PMID 40175188
·
Publisher ↗
Pulmonary arterial hypertension (PAH) and cancer may appear to be unrelated at first, but there is increasing evidence that they share many characteristics and complexities. Pulmonary vascular cells in PAH resemble cance...Pulmonary arterial hypertension (PAH) and cancer may appear to be unrelated at first, but there is increasing evidence that they share many characteristics and complexities. Pulmonary vascular cells in PAH resemble cancer cells in that they display abnormal growth patterns, resistance to cell death, metabolic changes, and channelopathies. These similarities open new possibilities for researchers and clinicians to apply cancer treatment strategies to PAH and possibly reverse the condition. This review explores the complex parallels between PAH and cancer, and emphasizes their similar channelopathy-like features at the molecular, cellular, and clinical levels. We also discuss the potential implications of these similarities for developing new treatments.
Frequent spillovers and recent geospatial expansion of avian influenza virus (AIV) pose significant economic and public health threats. Recent advances in vaccine technologies, bioinformatics, and artificial intelligence...Frequent spillovers and recent geospatial expansion of avian influenza virus (AIV) pose significant economic and public health threats. Recent advances in vaccine technologies, bioinformatics, and artificial intelligence will provide newer approaches to target genetically diverse and rapidly evolving AIVs. Here, we review recent advances in, and perspectives on, developing universal vaccines needed for the effective control of AIVs.
Trends Mol Med
· 2025 Apr · PMID 40133178
·
Full text
Aging and Alzheimer's disease (AD) exhibit sex differences in several biological processes, including demyelination. In a recent study, Lopez-Lee et al. uncover the contributions of sex chromosomes and gonadal hormones t...Aging and Alzheimer's disease (AD) exhibit sex differences in several biological processes, including demyelination. In a recent study, Lopez-Lee et al. uncover the contributions of sex chromosomes and gonadal hormones to sex differences in demyelination and identify Toll-like receptor 7 (TLR7) as a potential target to ameliorate tauopathy-induced demyelination in men.
Trends Mol Med
· 2025 Apr · PMID 40121135
·
Full text
Recent reports of gene therapy using autologous hematopoietic stem cell transplantation (HSCT) have addressed protein deficiencies of extra-hematopoietic origin. In a recent study, Srivastava et al. report that patients...Recent reports of gene therapy using autologous hematopoietic stem cell transplantation (HSCT) have addressed protein deficiencies of extra-hematopoietic origin. In a recent study, Srivastava et al. report that patients with hemophilia A receiving F8 lentiviral HSCT gene therapy achieved lasting factor VIII restoration and clinical improvement, marking an advance that could enable broader applications of HSCT.
Over the past 30 years, significant progress has been made in understanding the genetic causes of obesity. In the coming years, catalogs that map each genetic variant to its genomic function are expected to accelerate va...Over the past 30 years, significant progress has been made in understanding the genetic causes of obesity. In the coming years, catalogs that map each genetic variant to its genomic function are expected to accelerate variant-to-function (V2F) translation. Given that obesity is a heterogeneous disease, research will have to move beyond body mass index (BMI). Gene discovery efforts for more refined adiposity traits are poised to reveal additional genetic loci, pointing to new biological mechanisms. Obesity genetics research is reaching unprecedented heights and, along with a renewed interest in the development of weight-loss medication, it holds the potential to identify new drug targets. Polygenic scores (PGSs) that predict obesity risk are expected to further improve and will be particularly valuable early in life for timely prevention.
McFadden WM, Faerch M, Kirby KA
… +3 more, Dick RA, Torbett BE, Sarafianos SG
Trends Mol Med
· 2025 Sep · PMID 40021388
·
Full text
Antiretroviral therapy (ART) impairs viral replication in people living with HIV (PLWH) by suppressing infection or spread. However, not all treatment strategies apply to preventive applications like pre-exposure prophyl...Antiretroviral therapy (ART) impairs viral replication in people living with HIV (PLWH) by suppressing infection or spread. However, not all treatment strategies apply to preventive applications like pre-exposure prophylaxis (PrEP) for uninfected individuals. To prevent the establishment of HIV infection, PrEP must block viral replication either before, or at the stage of integration into the host genome. A promising PrEP approach under investigation utilizes lenacapavir (LEN), which targets the HIV-1 capsid protein (CA) potently before integration. LEN, a first-in-class antiretroviral, has shown high protective efficacy in the ongoing PURPOSE trials thus far. Here, we discuss clinical investigations of LEN, theoretical suitability of preclinical CA-binding antivirals in PrEP, and other key considerations for preventing HIV-1 infection by targeting the capsid.
Asparagine endopeptidase (AEP), or legumain, is a cysteine protease implicated in various disorders, including atherosclerosis, cancers, neurodegenerative diseases, and inflammation. The development of AEP inhibitors has...Asparagine endopeptidase (AEP), or legumain, is a cysteine protease implicated in various disorders, including atherosclerosis, cancers, neurodegenerative diseases, and inflammation. The development of AEP inhibitors has emerged as a promising therapeutic strategy to modulate AEP activity and slow disease progression. Various AEP inhibitors have been explored, encompassing small molecules, peptide-based, antibody-based, and natural inhibitors. Substrate-mimetic and covalent inhibitors show significant potential for selectively targeting AEP's active site, whereas noncovalent inhibitors offer reversible modulation. Additionally, FDA-approved drugs have also garnered attention for their diverse structures and multitarget capabilities. In this review, we summarize advancements in AEP inhibitors, their mechanisms of action, therapeutic applications in neurodegenerative diseases, and the challenges in translating these findings into clinical practice.
The ability to engineer immune cells yielded a transformative era in oncology. Early clinical trials demonstrated the efficacy of chimeric antigen receptor (CAR) T cells in resetting the immune system, motivating the exp...The ability to engineer immune cells yielded a transformative era in oncology. Early clinical trials demonstrated the efficacy of chimeric antigen receptor (CAR) T cells in resetting the immune system, motivating the expansion of this treatment beyond cancer, including autoimmune conditions. In this review, we discuss the current state of CAR T cell research in autoimmune diseases, examining the main challenges that limit widespread adoption of this therapy, such as complex isolation protocols, stringent immunosuppression, risk of secondary malignancies, and variable efficacy. We also review the studies addressing these limitations by development of off-the-shelf allogeneic CAR T cells, tunable safety systems, and antigen-specific therapies, which hold the potential to improve safety and accessibility of this treatment in clinical practice.
Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient deliver...Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.
Trends Mol Med
· 2025 Aug · PMID 39956738
·
Publisher ↗
Metabolomics has emerged as a transformative tool in precision oncology, with substantial potential for advancing biomarker discovery, monitoring treatment responses, and aiding drug development. Integrating artificial i...Metabolomics has emerged as a transformative tool in precision oncology, with substantial potential for advancing biomarker discovery, monitoring treatment responses, and aiding drug development. Integrating artificial intelligence (AI) into metabolomics optimizes data acquisition and analysis, facilitating the interpretation of complex metabolic networks and enabling more effective multiomics integration. In this opinion, we explore recent advances in the application of metabolomics within precision oncology, emphasizing the unique advantages that AI-driven metabolomics offers. We propose that AI not only complements but also amplifies the potential of current platforms, accelerating research progress and ultimately improving patient outcomes. Finally, we discuss the opportunities and challenges involved in translating AI-driven metabolomics into clinical practice for precision oncology.