Hyocholic acids (HCAs), synthesized by fetal CYP3A7, dominate the neonatal bile acid pool. By promoting regulatory T cells and suppressing T helper 17 cells, HCAs establish intestinal immune tolerance, guide healthy micr...Hyocholic acids (HCAs), synthesized by fetal CYP3A7, dominate the neonatal bile acid pool. By promoting regulatory T cells and suppressing T helper 17 cells, HCAs establish intestinal immune tolerance, guide healthy microbiota assembly, and protect infants from infections and gastrointestinal disorders (Zheng et al.).
Clonal hematopoiesis is emerging as a surprising modifier of Alzheimer's disease. Recent findings suggest that mutant myeloid cells may enter or expand within the brain, adopting either inflammatory or reparative states....Clonal hematopoiesis is emerging as a surprising modifier of Alzheimer's disease. Recent findings suggest that mutant myeloid cells may enter or expand within the brain, adopting either inflammatory or reparative states. We propose that their effects depend on the mutation, timing, clone size, brain niche, and disease stage.
Hepatocellular carcinoma (HCC) remains lethal due to its high refractoriness to standard treatment, which is contributed to by factors including adaptive metabolic reprogramming of HCC cells and pre-existing liver diseas...Hepatocellular carcinoma (HCC) remains lethal due to its high refractoriness to standard treatment, which is contributed to by factors including adaptive metabolic reprogramming of HCC cells and pre-existing liver diseases that compromise liver function. Abnormal tumor vasculature creates a nutrient-deprived microenvironment, intensifying competition between HCC cells and immune cells and impairing antitumor immunity. Among the complex metabolic network, amino acid (AA) metabolism emerges as a critical player and an attractive therapeutic target. This review first examines how dysregulated AA metabolism supports HCC hallmarks, including metabolic reprogramming and immune evasion. We discuss the translational potential of therapies targeting AA metabolism in HCC, ranging from pharmacologic inhibition to dietary AA intervention, which can be further integrated with existing HCC treatments to improve clinical outcomes.
By identifying graft ferroptosis as a druggable vulnerability, Veeckmans et al. show that FXT-001 intercepts lipid-radical injury during machine perfusion and improves liver and lung graft function. This work supports ra...By identifying graft ferroptosis as a druggable vulnerability, Veeckmans et al. show that FXT-001 intercepts lipid-radical injury during machine perfusion and improves liver and lung graft function. This work supports rather than proves machine perfusion as a therapeutic window for preimplantation graft repair, a concept that now requires postimplantation validation.
Tumor progression depends on coordinated adaptation of cancer cells and the tumor microenvironment to immune pressure, metabolic limitations, genomic instability, and biomechanical stress. While these adaptive responses...Tumor progression depends on coordinated adaptation of cancer cells and the tumor microenvironment to immune pressure, metabolic limitations, genomic instability, and biomechanical stress. While these adaptive responses have often been investigated through distinct experimental and conceptual frameworks, increasing evidence indicates that they converge on shared regulatory pathways. Calcium signaling is a fundamental regulator of cellular adaptation; however, its role in integrating tumor stress responses remains unclear. This review synthesizes emerging evidence identifying calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) as a key regulator linking calcium signaling to coordinated tumor and microenvironmental adaptation across mechanical, metabolic, replication, and immune stress responses. We discuss how CaMKK2 supports tumor ecosystem fitness through convergent tumor-intrinsic and microenvironmental programs and consider the therapeutic implications of targeting CaMKK2 and its signaling network, emphasizing context dependence, rational combination strategies, and biomarker-guided clinical translation.
Trends Mol Med
· 2026 Jun · PMID 42379944
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Gene therapy is evolving from gene addition to precise genome editing, enabling the direct correction of disease-causing mutations. Breakthrough technologies, such as clustered regularly interspaced short palindromic rep...Gene therapy is evolving from gene addition to precise genome editing, enabling the direct correction of disease-causing mutations. Breakthrough technologies, such as clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas) nucleases, base editors, prime editors, and CRISPR-associated transposases are reshaping the therapeutic landscape. This review covers the progression of precision editing technologies and their clinical applications, spanning from ex vivo therapies to in vivo treatments targeting vital organs. The rise of personalized medicine, highlighted by therapies, such as carbamoyl phosphate synthetase 1 editing, underscores the shift toward N-of-1 medicine for rare diseases. Clinical trial progress, delivery and accessibility challenges, and the role of AI in optimizing editing tools and predicting outcomes are also discussed. These innovations are transforming genetic medicine, offering the promise of safer, more durable, and personalized cures.
Trends Mol Med
· 2026 Jun · PMID 42362459
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Ischemia-reperfusion injury accelerates graft deterioration and limits the use of marginal donor organs. Recently, Veeckmans et al. showed that pharmacological ferroptosis inhibition preserves liver and lung graft functi...Ischemia-reperfusion injury accelerates graft deterioration and limits the use of marginal donor organs. Recently, Veeckmans et al. showed that pharmacological ferroptosis inhibition preserves liver and lung graft function across porcine and human perfusion platforms, positioning lipid peroxidation-driven cell death as an actionable target in machine perfusion-era transplantation.
Trends Mol Med
· 2026 Jun · PMID 42309896
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Aging affects virtually all organs and biological processes, and age-related diseases remain the leading causes of death worldwide. Genetic factors play a central role in modulating lifespan, and discoveries in the genet...Aging affects virtually all organs and biological processes, and age-related diseases remain the leading causes of death worldwide. Genetic factors play a central role in modulating lifespan, and discoveries in the genetic manipulation of the aging process in animal models have transformed our perception of aging. However, translating these findings into clinical therapies remains challenging. Recent breakthroughs demonstrate that gene therapies can directly target aging mechanisms. Single-gene therapies have ameliorated multiple age-related pathologies, such as pediatric Parkinson disease. In this review, we discuss recent advances and prospects for developing gene therapies for aging and age-related diseases, highlighting potential targets, delivery strategies, cellular rejuvenation, and lessons from long-lived species. Despite remaining challenges, longevity gene therapy offers a promising avenue to reprogram aging and delay age-related decline.
Palomer X, Rodríguez-Calvo R, García-Mateo S
… +2 more, Wahli W, Vázquez-Carrera M
Trends Mol Med
· 2026 Jun · PMID 42285879
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Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by autoimmune-mediated destruction of intrahepatic bile ducts, leading to fibrosis, cirrhosis, and liver failure. Ursodeoxycholic aci...Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease characterized by autoimmune-mediated destruction of intrahepatic bile ducts, leading to fibrosis, cirrhosis, and liver failure. Ursodeoxycholic acid remains the first-line treatment, but up to 40% of patients respond inadequately and continue to experience fatigue and pruritus. This therapeutic gap has recently been addressed by the approval of two new drugs, elafibranor and seladelpar, which activate peroxisome proliferator-activated receptors (PPARs). This review explores recently unveiled molecular mechanisms underlying the effectiveness of PPAR-targeting drugs in PBC, focusing on their effects on cellular immune regulation, bile acid production and toxicity, and hepatic fibrosis. Additionally, we examine current knowledge and ongoing challenges that will influence the roles of PPAR agonists in improving PBC treatment.
Trends Mol Med
· 2026 Jun · PMID 42259704
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Hepatocellular carcinoma (HCC) arises within an immunologically complex, tolerogenic microenvironment, where CD4 CD25 Foxp3 regulatory T cells (Tregs) suppress antitumor immunity, sustain inflammation, and promote pathol...Hepatocellular carcinoma (HCC) arises within an immunologically complex, tolerogenic microenvironment, where CD4 CD25 Foxp3 regulatory T cells (Tregs) suppress antitumor immunity, sustain inflammation, and promote pathological angiogenesis and tumor progression. We delineate how the unique metabolic and cytokine landscapes of HCC stabilize highly suppressive Treg subsets and highlight phenotypic and metabolic differences between Tregs driven by viral versus nonviral liver diseases. We discuss Treg heterogeneity and the prognostic and predictive value of circulating and intratumoral Treg metrics, together with emerging strategies to target tumor-resident Tregs while preserving peripheral tolerance. Finally, we examine how modern combination immunotherapies reshape Treg dynamics, emphasizing the need to balance enhanced antitumor efficacy with the risk of immune-related liver and systemic toxicities.
Trends Mol Med
· 2026 Jun · PMID 42259703
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Why do half of all children with Down syndrome have heart defects? Recent studies show that multiple chromosome 21 genes-most notably the chromatin regulator high-mobility group nucleosome-binding domain 1-collectively d...Why do half of all children with Down syndrome have heart defects? Recent studies show that multiple chromosome 21 genes-most notably the chromatin regulator high-mobility group nucleosome-binding domain 1-collectively disrupt bone morphogenetic protein, Wingless/Integrated, Neurogenic locus notch homolog, and calcineurin-nuclear factor of activated T cells signalling. In this forum, we propose a convergent threshold model for these cardiac malformations.
Trends Mol Med
· 2026 Jun · PMID 42243035
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Neurodegenerative diseases with prominent motor symptoms converge on mitochondrial and lysosomal bottlenecks in selectively vulnerable neurons. Deubiquitinases regulate ubiquitin-dependent organelle fate at these decisio...Neurodegenerative diseases with prominent motor symptoms converge on mitochondrial and lysosomal bottlenecks in selectively vulnerable neurons. Deubiquitinases regulate ubiquitin-dependent organelle fate at these decision points. Emerging evidence suggests that modulating deubiquitinase activity can restore organelle quality control and represents a promising therapeutic strategy.
Lorito N, Bonechi F, Romano E
… +2 more, Smiriglia A, Morandi A
Trends Mol Med
· 2026 Jun · PMID 42236357
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Therapy resistance is a major obstacle to durable clinical responses. While genetic alterations and signalling rewiring are primary drivers of resistance, metabolic adaptation, which is closely intertwined with these pro...Therapy resistance is a major obstacle to durable clinical responses. While genetic alterations and signalling rewiring are primary drivers of resistance, metabolic adaptation, which is closely intertwined with these processes, enables tumour persistence under therapeutic pressure and directly contributes to resistance. Peroxisomes are metabolic organelles with a role in controlling lipid metabolism, together with redox signalling and homeostasis-processes that intersect with pathways governing cancer behaviour and therapy response. Indeed, peroxisomal functions are remodelled to support metabolic plasticity and redox buffering under therapeutic stress. In this review, we synthesise emerging evidence linking peroxisome biology to resistance to chemotherapy, targeted therapies, radiotherapy, and immunotherapy and discuss how peroxisomal pathways may be exploited therapeutically or as biomarkers to overcome cancer therapy resistance.
Trends Mol Med
· 2026 Jun · PMID 42236356
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Most solid tumors remain immunologically 'cold' and refractory to therapy, making immunogenic cell death (ICD) induction a central therapeutic goal. Z-DNA binding protein 1 (ZBP1) acts as a sensor, converting intrinsic n...Most solid tumors remain immunologically 'cold' and refractory to therapy, making immunogenic cell death (ICD) induction a central therapeutic goal. Z-DNA binding protein 1 (ZBP1) acts as a sensor, converting intrinsic nucleic acid stress into ICD programs. This review establishes ZBP1 as a convergence point linking distinct nucleic acid stress signals, including DNA damage response, telomere crisis, replication stress, dysregulated RNA splicing, endogenous retroelement re-expression, and mitochondrial stress response, to PANoptosis. We highlight recent therapeutic strategies, ranging from biological inducers and direct agonists to Z-DNA proteolysis targeting chimeras and pharmacological stressors, that harness nucleic acid stress responses to engage ZBP1. Finally, we propose a translational roadmap emphasizing combination strategies and biomarker-guided patient selection to engage the ZBP1 signaling axis and promote durable antitumor immunity.
Roufosse C, Bouricha O, Burrell A
… +4 more, Prendecki M, Turajlic S, Turner-Stokes T, Collinson L
Trends Mol Med
· 2026 May · PMID 42209398
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Immune cells mediate acute and chronic renal failure in native and transplanted kidneys, initiating auto- and allo-immunity, and acting as effectors in other diseases such as diabetes, hypertension, and cancer. Many drug...Immune cells mediate acute and chronic renal failure in native and transplanted kidneys, initiating auto- and allo-immunity, and acting as effectors in other diseases such as diabetes, hypertension, and cancer. Many drugs already in use or in development for these diseases target the putative immune mechanisms at play, based on in vitro cell experiments and animal models. Here, we review how recent and upcoming advanced tissue imaging techniques-many of them applicable to human kidney samples as well as animal models-could further improve drug development by providing insights into immune cell types, activation states, and behaviours in kidney disease. We illustrate an innovative cross-scale multimodal imaging pipeline and its application to the investigation of immune cells in human kidney samples.
Trends Mol Med
· 2026 May · PMID 42135164
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Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the leading causes of hepatocellular carcinoma (HCC), yet the mechanisms of tumor microenvironment (TME)-metabolic crosstalk remain incom...Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the leading causes of hepatocellular carcinoma (HCC), yet the mechanisms of tumor microenvironment (TME)-metabolic crosstalk remain incomplete. This review summarizes the current understanding of the bidirectional interaction between TME remodeling and metabolic reprogramming in MASLD-related HCC. We discuss how chronic inflammation, lipotoxicity, and oxidative stress reshape the TME, elaborate on key metabolic pathways, and highlight emerging metabolomic profiling approaches. The interplay between immune cells and metabolic changes fosters immunosuppressive tumor niches. Metabolomic biomarkers arising from TME-metabolic interactions are vital for disease progression and therapeutic resistance. This integrated view underscores the potential of metabolomic biomarkers for early diagnosis, disease stratification, and personalized therapies, advancing precision medicine in MASLD-related HCC.
Trends Mol Med
· 2026 May · PMID 42115085
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TANGO2 deficiency disorder (TDD) is an ultrarare, autosomal recessive disease characterized by neuromuscular impairment, intellectual disability, and recurrent metabolic crises leading to life-threatening ventricular arr...TANGO2 deficiency disorder (TDD) is an ultrarare, autosomal recessive disease characterized by neuromuscular impairment, intellectual disability, and recurrent metabolic crises leading to life-threatening ventricular arrhythmias. Intrafamilial phenotypic variability and overlapping manifestations with other metabolic diseases complicate timely and accurate diagnosis. This review summarizes the clinical spectrum and emerging molecular mechanisms of TDD, integrating insights from structural biology and experimental disease models. Evidence suggests that high-dose vitamin B complex supplementation can reduce the frequency of metabolic crises and improve neurocognitive outcomes, underscoring the importance of early diagnosis and intervention. By integrating recent advances, this review aims to provide a thorough understanding of TANGO2 deficiency, identify key unmet needs, and define future research priorities.