Lu E, Chidambaram V, Kumar A
… +5 more, Cotto Aparicio HG, Golzar Y, Pyslar N, Mehta JL, Karakousis PC
Trends Mol Med
· 2026 Feb · PMID 40885619
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Antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable condition; however, people living with HIV (PLWH) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Impaired c...Antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable condition; however, people living with HIV (PLWH) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Impaired cholesterol efflux due to dysfunction of macrophage lipid transporters and high-density lipoprotein (HDL) is an important mechanism in HIV-associated atherosclerosis. HIV Nef protein inhibits ATP-binding cassette transporter (ABC)A1-mediated cholesterol efflux via post-transcriptional downregulation, mislocalization, and enhanced degradation. Although ART partially improves macrophage and HDL functionality through viral suppression, cholesterol efflux impairment persists. Emerging therapies, including nuclear receptor agonists, apolipoprotein mimetics, and HDL-based nanoparticles, offer dual benefits by enhancing reverse cholesterol transport and reducing HIV replication. In this review, we explore the molecular mechanisms of HIV-induced cholesterol efflux impairment and potential therapies targeting ASCVD risk in HIV.
Trends Mol Med
· 2026 Mar · PMID 40846612
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The muscle regeneration niche comprises various cell types, including muscle stem cells (MuSCs; also termed satellite cells), immune cells, and stromal cells, all of which have crucial roles in the regeneration process....The muscle regeneration niche comprises various cell types, including muscle stem cells (MuSCs; also termed satellite cells), immune cells, and stromal cells, all of which have crucial roles in the regeneration process. Intracellular metabolic reprogramming during injury responses is closely linked to the functional activities of these cells, thus necessitating a comprehensive understanding for developing targeted metabolic interventions that promote regeneration. Recent studies have suggested the existence of a more intricate network, involving cell-cell metabolic crosstalk and even cross-organ regulation, which underpins muscle regeneration. In addition, aging and diseases that disrupt overall metabolic homeostasis contribute to muscle dysfunction, due, in part, to metabolic disorders in the regeneration niche. In this review, we provide a comprehensive overview of the metabolic profile within the muscle regeneration niche and highlight potential interventions to reprogram metabolism to improve regenerative capacity.
Kumari B, Hussain NF, Kennedy SH
… +3 more, Papageorghiou AT, Das JK, Bhutta ZA
Trends Mol Med
· 2025 Nov · PMID 40796454
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The Supporting Women in Science (SWIS) program aims to strengthen female representation in research in developing countries. This article highlights the program participation, mentorship challenges, and systemic barriers...The Supporting Women in Science (SWIS) program aims to strengthen female representation in research in developing countries. This article highlights the program participation, mentorship challenges, and systemic barriers. Findings inform inclusive, discipline-specific strategies designed to support women's research capacity, academic leadership, and advancement in the global scientific community.
Hönigova K, Hadrava Vanova K, Raudenska M
… +5 more, Uher O, Kejik Z, Jakubek M, Masarik M, Pacak K
Trends Mol Med
· 2026 Feb · PMID 40769853
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Preventing metastasis remains a major challenge in cancer therapy. Effective strategies should combine immune activation with the inhibition of cancer cell migration and invasion. In this Opinion article, we propose a mu...Preventing metastasis remains a major challenge in cancer therapy. Effective strategies should combine immune activation with the inhibition of cancer cell migration and invasion. In this Opinion article, we propose a multimodal approach that integrates migrastatic agents with photodynamic therapy (PDT) and intratumoral immunotherapy (ITI). Migrastatics inhibit cell motility and may reduce the risk of tumor cell dissemination. PDT promotes immunogenic cell death and enhances immune recognition while minimizing damage to healthy tissues. ITI delivers immune stimulants directly into tumors to stimulate local immune responses. This therapeutic strategy could suppress cancer cell plasticity, limit metastasis, and activate antitumor immunity, potentially improving outcomes in cancers prone to early invasion. This comprehensive approach is discussed in the context of current clinical practice.
Trends Mol Med
· 2026 May · PMID 40744833
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Prostate cancer, the most prevalent noncutaneous cancer and the second leading cause of cancer death among men, is highly heritable. Germline alterations in genes involved in DNA damage repair and the androgen synthesis...Prostate cancer, the most prevalent noncutaneous cancer and the second leading cause of cancer death among men, is highly heritable. Germline alterations in genes involved in DNA damage repair and the androgen synthesis pathway are associated with worse outcomes. Pathogenic variants in BRCA1, BRCA2, and HSD3B1 are the most prevalent alterations in men with advanced prostate cancer and are associated with increased risk of disease development and progression. These variants are pharmacologically actionable. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown survival benefits in carriers of BRCA1/2 mutations, while HSD3B1 adrenal-permissive carriers might benefit from early intensified androgen blockade treatment. This review explores the impact of pathogenic germline alterations associated with prostate cancer, with a focus on common, clinically actionable variants.
Trends Mol Med
· 2026 Feb · PMID 40744832
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Emerging evidence, supported by clinical responses to immunotherapy and the recapitulation of sensory symptoms in passive transfer models, shows that autoantibodies (AAbs) may drive neuropathic pain. These findings highl...Emerging evidence, supported by clinical responses to immunotherapy and the recapitulation of sensory symptoms in passive transfer models, shows that autoantibodies (AAbs) may drive neuropathic pain. These findings highlight the importance of immune profiling to enhance diagnosis and treatment, and provide molecular insights into broader pain mechanisms in clinical contexts.
Correia-Rodrigues Â, Ribeiro-Rodrigues T, Gonçalves L
… +3 more, Almeida JP, Ferreira MJ, Girao H
Trends Mol Med
· 2026 Jan · PMID 40731211
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Amyloid transthyretin (ATTR) amyloidosis is a progressive and multifaceted disorder characterized by extracellular deposition of misfolded transthyretin (TTR) in tissues, leading to irreversible damage. The rising preval...Amyloid transthyretin (ATTR) amyloidosis is a progressive and multifaceted disorder characterized by extracellular deposition of misfolded transthyretin (TTR) in tissues, leading to irreversible damage. The rising prevalence of this disease underscores the urgent need for a deeper understanding of its complex pathology to improve diagnosis and treatment strategies. This Review explores the cellular and molecular mechanisms underlying ATTR cardiac amyloidosis (ATTR-CA), delving into the processes driving disease progression, exploring the recent progress in the experimental models used to study ATTR-CA, and highlights advances in diagnostic tools and therapeutic strategies. By integrating the latest insights, this Review aims to provide a holistic and comprehensive understanding of ATTR-CA, offering an integrated perspective on research progresses and improvements in patient outcomes.
Trends Mol Med
· 2026 Feb · PMID 40713320
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Nicotinamide adenine dinucleotide (NAD) is an essential cofactor for hundreds of biochemical reactions. Targeting NAD metabolism has been investigated as a therapeutic strategy for various metabolic, neurogenerative, and...Nicotinamide adenine dinucleotide (NAD) is an essential cofactor for hundreds of biochemical reactions. Targeting NAD metabolism has been investigated as a therapeutic strategy for various metabolic, neurogenerative, and inflammatory conditions, including aging and cancer. Here we highlight recent advances in host-microbiome interactions regulating NAD metabolism and discuss their therapeutic potential.
Trends Mol Med
· 2026 Feb · PMID 40653413
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RNA immunotherapy offers a versatile and scalable platform for reprogramming immune responses in cancer and autoimmunity. Advances in linear mRNA, self-amplifying RNA (saRNA), and circular RNA (circRNA) enable the progra...RNA immunotherapy offers a versatile and scalable platform for reprogramming immune responses in cancer and autoimmunity. Advances in linear mRNA, self-amplifying RNA (saRNA), and circular RNA (circRNA) enable the programmable delivery of therapeutic proteins with improved stability, expression, and targeting. In cancer, RNA platforms have shown clinical promise in neoantigen vaccines, cytokine therapies, and chimeric antigen receptor (CAR) immune cell engineering. In autoimmunity, RNA strategies are being developed to induce antigen-specific tolerance, expand regulatory T cells (Tregs), and deliver anti-inflammatory mediators. Structural optimizations and targeted delivery systems further enhance therapeutic efficacy and safety. This review discusses recent clinical progress, mechanistic foundations, and emerging directions for RNA immunotherapy as a broadly applicable platform across cancer and autoimmune disease contexts.
Asif S, Kinzel M, Vanderhyden B
… +2 more, Jacquelot N, Ardolino M
Trends Mol Med
· 2026 Mar · PMID 40651913
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Group 2 innate lymphoid cells (ILC2s) are emerging players in tumor immunity. ILC2 heterogeneity confers tissue-specific outcomes, with sometimes opposing effects on the prognosis and progression of various cancers. The...Group 2 innate lymphoid cells (ILC2s) are emerging players in tumor immunity. ILC2 heterogeneity confers tissue-specific outcomes, with sometimes opposing effects on the prognosis and progression of various cancers. The role of ILC2s in breast and ovarian cancer is an active area of investigation, with research aimed at leveraging these cells to enhance immunotherapy.
Trends Mol Med
· 2026 Feb · PMID 40645854
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Bone homeostasis relies on the coordinated activity of osteoblasts and osteoclasts that balances bone formation and resorption, and of osteocytes for biomechanical sensing and hormone secretion. A key factor in the funct...Bone homeostasis relies on the coordinated activity of osteoblasts and osteoclasts that balances bone formation and resorption, and of osteocytes for biomechanical sensing and hormone secretion. A key factor in the function of these cells is proteostasis, where the endoplasmic reticulum (ER) oversees protein synthesis, quality control, folding, and the secretion of proteins such as collagen type I. Emerging research links ER proteostasis defects to skeletal disorders caused by impaired bone development and mass. We explore the mechanisms of ER proteostasis, including the unfolded protein response (UPR), and discuss how genetic, metabolic, and environmental factors disrupt these pathways and contribute to bone pathology. We also highlight the need for further mechanistic insights which could pave the way for novel therapies that target ER-Golgi traffic and inhibit ER stress in bone diseases.
Trends Mol Med
· 2025 Dec · PMID 40645853
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The 2022 World Health Organization and International Consensus Classification (WHO/ICC 2022) diagnostic classifications for hematological malignancies remain focused on cancer cell characteristics, largely neglecting the...The 2022 World Health Organization and International Consensus Classification (WHO/ICC 2022) diagnostic classifications for hematological malignancies remain focused on cancer cell characteristics, largely neglecting the immune environment. This disconnection limits diagnostic accuracy and the potential for tailored and individualized therapeutic intervention. The potential for exploiting the nonmalignant immune compartment as therapy targets (e.g., bispecific antibodies) or biomarkers of patient outcomes, should be included in guiding clinical decision making. To bridge this gap, distinct immune profile classifications, such as inflammatory subtypes, need standardized definitions. Next-generation profiling technologies - including single-cell sequencing, spatial transcriptomics, and advanced cytometry - should be integrated into clinical workflows or translated into practical diagnostic tools. Therefore, next-generation immune profiling for hematological malignancies goes beyond the cancer cells - enabling improved disease classification and precision immunotherapies.
Trends Mol Med
· 2026 Jan · PMID 40640031
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Systemic lupus erythematosus (SLE, lupus) remains an enigmatic diagnosis with a poor prognosis. SLE is characterised by complex biology and heterogeneous clinical manifestations that create a major hurdle to the approval...Systemic lupus erythematosus (SLE, lupus) remains an enigmatic diagnosis with a poor prognosis. SLE is characterised by complex biology and heterogeneous clinical manifestations that create a major hurdle to the approval of new medicines and contribute to multiple trial failures. While the pace of research has accelerated, drugs currently in development target a limited spectrum of mechanisms, tempering hope that any will be a panacea. The pace of translation lags behind advances in basic science, and this continues to cost patients dearly. The unacceptable metabolic adverse effects of glucocorticoids have rightly driven treatment guidelines towards ever more stringent dose-reduction targets, and new research is ongoing to develop a safe and reliable glucocorticoid replacement that will be active across a breadth of inflammatory pathways.
Bomfim GHS, Dupont G, Wright T
… +2 more, Mighell A, Lacruz RS
Trends Mol Med
· 2026 Feb · PMID 40617756
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Dental enamel protects against the invasion of bacterial pathogens deep into the innervated layers of the tooth. Hereditary enamel disorders referred to as amelogenesis imperfecta (AI) can severely affect the development...Dental enamel protects against the invasion of bacterial pathogens deep into the innervated layers of the tooth. Hereditary enamel disorders referred to as amelogenesis imperfecta (AI) can severely affect the development and mineralization of dental enamel compromising these functions. This rare disorder is often visible, carries a significant psychological and financial burden, and cosegregates with disease in other organs. Pathological variants in over 100 genes affect the enamel formation. Here, we describe the biology of enamel formation focusing on pathogenic variants underlying AI. We provide a computational model encapsulating new advances in calcium regulation during enamel formation. We also describe the psychological and financial burden of AI, its impact in systemic health, and discuss recent developments in diagnostic panels to detect AI.
Albrecht P, Karabati E, Ebert MP
… +1 more, Betge J
Trends Mol Med
· 2025 Dec · PMID 40555635
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Gastric cancer (GC) remains a deadly disease because of late detection and limited treatment options at advanced stages. Treatment of patients with metastatic disease is based on chemotherapy, complemented by antibodies...Gastric cancer (GC) remains a deadly disease because of late detection and limited treatment options at advanced stages. Treatment of patients with metastatic disease is based on chemotherapy, complemented by antibodies targeting HER2, VEGFR2, and more recently PD-1 or claudin 18.2. Further targets, such as FGFR2b, as well as novel drug classes including antibody-drug conjugates (ADCs) and bispecific antibodies, are promising developments in GC treatment. Despite the failure of several targeted agents, the landscape of GC therapy is evolving rapidly, facilitated by umbrella or platform precision medicine trials. The integration of next-generation sequencing and other omics techniques into molecular tumor boards, as well as functional drug testing on patient-derived models, might bring us closer to personalized oncology and ultimately improve patient survival.
Xiao Y, Wu B, Zhou Q
… +4 more, Wu F, Li N, Xu C, Han X
Trends Mol Med
· 2025 Nov · PMID 40541461
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Ex vivo chimeric antigen receptor (CAR) T cell therapy has achieved clinical success in hematological malignancies; yet, viral transduction risks insertional mutagenesis. Developing safe and efficient nonviral approaches...Ex vivo chimeric antigen receptor (CAR) T cell therapy has achieved clinical success in hematological malignancies; yet, viral transduction risks insertional mutagenesis. Developing safe and efficient nonviral approaches for the genetic engineering of T cells and other immune cells is the key to next-generation immunotherapy for cancer and noncancerous diseases. mRNA is an emerging modality for CAR engineering because of its transient expression and minimal risks. As a clinically validated nonviral vector, lipid nanoparticles (LNPs) are gaining popularity for ex vivo/in vivo mRNA-based CAR engineering of immune cells, making cell therapy safer and affordable. This review discusses the progress, delivery approaches, and challenges of CAR therapy and highlights mRNA-LNP advancements in shaping future CAR immune cell therapy for oncology and non-oncology.
Trends Mol Med
· 2025 Nov · PMID 40537350
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Interleukin (IL)-15 engineering in chimeric antigen receptor (CAR)-cell therapy has demonstrated promising antitumor efficacy against both hematological malignancies and solid tumors in recent clinical trials. However, i...Interleukin (IL)-15 engineering in chimeric antigen receptor (CAR)-cell therapy has demonstrated promising antitumor efficacy against both hematological malignancies and solid tumors in recent clinical trials. However, increased cytokine release syndrome (CRS) toxicity is primarily observed in conventional CAR-T cells, underscoring the need to balance safety and efficacy in IL-15-enhanced CAR therapy for clinical application.