Biochemical Society Transactions[JOURNAL]
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200 papers
TDP-43 proteinopathy as a biomarker and therapeutic target in amyotrophic lateral sclerosis.
Christoforidou E, McFagan E, McLaughlin M … +1 more , Hafezparast M
Biochem Soc Trans · 2026 Jul · PMID 42383305 · Full text
Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding...
Amyotrophic lateral sclerosis (ALS) is the most common form of adult-onset motor neuron disease, characterised by the degeneration of upper and lower motor neurons. The cytoplasmic aggregation of TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein, is considered a hallmark of ALS pathology, found in nearly all postmortem cases of ALS. TDP-43 is normally primarily nuclear, where it has a widespread role in gene regulation. Mutations, extrinsic stressors, and alterations in RNA homeostasis in ALS lead to nuclear depletion of TDP-43 and the formation of cytosolic TDP-43 aggregates. This causes multiple downstream effects on neuronal function and degeneration as well as gene expression. TDP-43 is a promising target as a biomarker, as it is found to be elevated in the biofluids of ALS patients, and its cytoplasmic aggregation can also be observed in peripheral tissues; however, methodological variability and technical limitations currently preclude the establishment of TDP-43 as a standalone biomarker. There are also promising therapeutic strategies in development targeting TDP-43 pathology, but a critical challenge that remains is achieving a balance between eliminating toxic aggregates and preserving the essential functions of TDP-43. In summary, with further research, considering TDP-43 pathology in ALS gives hope for finding future novel diagnostics and therapeutics for ALS.
Advancing the monitoring of organelle contact sites in vitro and in vivo.
Barazzuol L, Peggion C, Brini M … +2 more , Nasu Y, Calì T
Biochem Soc Trans · 2026 Jul · PMID 42370464 · Full text
Organelle contact sites are highly dynamic and specialized regions where distinct organelles come into proximity, enabling direct inter-organelle communication. These structures play fundamental roles in cellular homeost...
Organelle contact sites are highly dynamic and specialized regions where distinct organelles come into proximity, enabling direct inter-organelle communication. These structures play fundamental roles in cellular homeostasis by coordinating the exchange of lipids, metabolites, and ions, as well as regulating key processes such as organelle dynamics, mitochondrial fission, autophagy, and metabolic integration. Alterations in contact site architecture and function have been increasingly associated with a wide range of human diseases, including neurodegeneration, metabolic disorders, and cancer. Despite their biological relevance, the nanoscale nature and dynamic behaviour of contact sites have historically posed significant challenges for their accurate detection and functional characterization. Here, we provide a comprehensive overview of the methodologies currently available to study organelle contact sites, ranging from classical approaches such as electron microscopy and biochemical fractionation to advanced imaging techniques and genetically encoded reporters. We discuss recent developments in high-resolution and live-cell microscopy that have improved the spatial and temporal resolution of contact site analysis, as well as emerging tools designed to selectively label, quantify, and manipulate these interfaces. Attention is given to the next generation of engineered reporters capable of sensing molecular and ionic exchanges at contact sites, thereby moving beyond structural description toward functional interrogation. By critically evaluating the strengths and limitations of existing approaches, we aim to provide a framework for selecting appropriate tools and to highlight future directions in the field. Ultimately, advancing our ability to monitor and dissect organelle contact sites will be essential for understanding their contribution to cellular physiology and disease.
Mechanisms influencing transient cytoplasmic protein targeting to intracellular lipid droplets.
Laws JL, Monson EA, Wallace LA … +2 more , Helbig KJ, Reddington CJ
Biochem Soc Trans · 2026 Jul · PMID 42370463 · Full text
Lipid droplets (LDs) have a multitude of functions ranging from lipid storage to fighting infection and are decorated with a variety of proteins on their surface that determine their functions and behaviours. Mass spectr...
Lipid droplets (LDs) have a multitude of functions ranging from lipid storage to fighting infection and are decorated with a variety of proteins on their surface that determine their functions and behaviours. Mass spectrometric analysis has identified the vast array of LD-localised proteins, which have recently been shown to be dynamic, changing in response to cellular stress, infection, and altered homeostasis. Here, we review the key mechanisms of cytoplasmic protein interactions with the LD, highlighting conventional features like amphipathic helices, atypical sequence-based motifs, protein-protein interactions, and post-translational modifications that confer dynamic targeting of proteins to the surface of the LD. A better understanding of the transient LD proteome and the mechanisms that confer LD protein targeting will allow researchers to develop a more thorough understanding of LD biology, and the role of LDs in cellular homeostasis and disease.
Replication associated nuclear DNA mismatch repair across kingdoms.
Spampinato CP, Giri J
Biochem Soc Trans · 2026 Jul · PMID 42345189 · Full text
The mismatch repair (MMR) system is an essential DNA repair mechanism that recognizes and corrects single base-base mismatches and unpaired nucleotides that escaped the proofreading exonuclease activity of DNA polymerase...
The mismatch repair (MMR) system is an essential DNA repair mechanism that recognizes and corrects single base-base mismatches and unpaired nucleotides that escaped the proofreading exonuclease activity of DNA polymerases or recombination intermediates. This pathway is highly conserved throughout evolution. However, the nature and number of MMR proteins differ between eukaryotes and prokaryotes. Even more, the plant MMR system contains an ancient duplicated MMR protein. In addition, developmental processes vary among eukaryotic organisms. One striking feature is plant genome stability maintenance over multiple generations because embryogenesis and seed development occur after many divisions during plant vegetative growth. Thus, it was of our interest to review the present state of knowledge with respect to the MMR mechanism from eukaryotic organisms, with special comparisons between human, yeast, and plant systems.
Phosphatases of regenerating liver downregulate PTEN to promote tumorigenesis.
Abou-Shanab AM, Yu J, Bai Y … +1 more , Zhang ZY
Biochem Soc Trans · 2026 Jul · PMID 42345188 · Full text
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the most frequently inactivated tumor suppressors in human cancers, serving as a critical negative regulator of phosphatidylinositol 3-kinase (...
The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is one of the most frequently inactivated tumor suppressors in human cancers, serving as a critical negative regulator of phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Although genetic mutation or deletion commonly underlie functional PTEN loss, accumulating evidence indicates that post-transcriptional and post-translational mechanisms also substantially contribute to PTEN suppression. Phosphatases of regenerating liver (PRLs), comprising PRL1, PRL2, and PRL3, are oncogenic phosphatases frequently overexpressed in both solid and hematological malignancies. Emerging studies reveal that PRLs can downregulate PTEN through a post-translational mechanism by direct dephosphorylation of PTEN at Tyr336, therefore promoting PTEN ubiquitination and proteasomal degradation. PRLs can also reduce PTEN expression through a post-transcriptional mechanism by dephosphorylating the inhibitory Tyr570 in JAK2, thereby activating the JAK2/STAT3-mediated miR-21 expression. These coordinated actions collectively amplify PI3K-AKT signaling, consequently promoting proliferation, survival, and metastasis. In the present review, we synthesize current knowledge of PRL structure, evolution, and functional diversity, evaluate genetic, biochemical, and organismal evidence linking PRLs to PTEN regulation, and discuss insights on PRL oncogenicity derived from experimental models. We further examine context-dependent functions of PRLs, unresolved questions regarding catalytic versus scaffold activities, and the therapeutic potential of targeting the PRL-PTEN axis. Understanding how PRLs modulate PTEN activity may reveal new strategies to restore tumor suppressor function in PTEN-deficient cancers.
Implications of Rho GTPase signaling in cancer immunotherapy.
Cai M, Guo F, Zheng Y
Biochem Soc Trans · 2026 Jul · PMID 42339915 · Full text
Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimera-antigen receptor (CAR)-T cell therapy, has achieved substantial clinical success. However, response rates remain limited in many patients du...
Cancer immunotherapy, including immune checkpoint inhibitors (ICIs) and chimera-antigen receptor (CAR)-T cell therapy, has achieved substantial clinical success. However, response rates remain limited in many patients due to tumor-intrinsic immune evasion and immune cell dysfunction within the tumor microenvironment (TME). Rho family small GTPases are key signaling regulators of cytoskeletal dynamics, intracellular trafficking, transcription, and metabolism in cancers. Emerging evidence implicates Rho GTPase signaling in mediating immunotherapy efficiency through its context-dependent functions. Individual Rho GTPases modulate immunotherapy responses in tumor cells and various immune cells through actomyosin-mediated chemotaxis, cell junctions, cell polarity, and gene/epigenetic networks, among other pathways. The present review summarizes both the direct evidence linking Rho GTPases in tumor cells to immunotherapy responses and the indirect role of the selective Rho GTPase signaling network in various immune cells, with a focus on the recent progress in understanding the molecular mechanisms and associated outcomes of the ICIs and CAR-T cell therapies. We highlight current knowledge gaps at the intersection of Rho GTPase biology and cancer immunology and discuss therapeutic implications, proposing that selective modulation of specific Rho GTPase signaling pathways in tumor or TME immune cells represents a promising strategy to improve immunotherapy efficiency.
Theme and variations: activation and regulation of gasdermin-mediated inflammation.
Rothera EY, Horam S, Hu Y … +3 more , Lin SA, David AJ, Xiao TS
Biochem Soc Trans · 2026 Jul · PMID 42339914 · Full text
Gasdermins are effectors for pyroptosis, a highly inflammatory form of cell death. Mammalian gasdermin (GSDM) family members harbor N-terminal domains (NTDs) that bind membrane phospholipids and assemble oligomeric pores...
Gasdermins are effectors for pyroptosis, a highly inflammatory form of cell death. Mammalian gasdermin (GSDM) family members harbor N-terminal domains (NTDs) that bind membrane phospholipids and assemble oligomeric pores. Their C-terminal domains are regulatory modules, which suppress the cytolytic function of the NTDs under homeostatic conditions, and in several cases mediate the recruitment of proteases that cleave GSDMs following upstream signaling. The initial model for gasdermin activation was that upon protease processing their NTDs localize to the plasma membrane to assemble oligomeric pores and mediate pyroptosis. Emerging evidence suggests fascinating variations of this paradigm. For example, cleavage-independent pyroptotic activities have been reported for several family members that undergo post-translational modifications such as S-acylation, PARylation, oxidation, or phosphorylation. Furthermore, some gasdermins associate with membranes from organelles such as mitochondria, and often play non-pyroptotic roles in cellular physiology. In the present mini-review, we briefly summarize the molecular mechanisms governing the activation of different gasdermin family members, focusing on protease processing as the most well-studied mechanism. This is followed by discussion of two aspects of gasdermin biology. Namely, cleavage-independent pyroptotic activities and the localization of gasdermins at mitochondria and nucleus implicated in pyroptotic and non-pyroptotic functions. The diverse mechanisms of gasdermin activation and regulation in response to different upstream signaling pathways demonstrate the versatility of this conserved family of pore-forming proteins in various aspects of cellular physiology throughout evolution. The pleiotropic functions of gasdermins in inflammatory disorders, antimicrobial defense, antitumor immunity, neurodegenerative disorders etc., suggest fertile ground for exploration of therapeutic avenues.
Non-canonical subunit functions in multiprotein complexes: insights from the Mediator complex.
Verger A, Monté D, Villeret V
Biochem Soc Trans · 2026 Jun · PMID 42325198 · Full text
The Mediator complex is a central regulator of RNA polymerase II transcription, integrating signals from transcription factors and coordinating pre-initiation complex assembly. Beyond this canonical role, numerous studie...
The Mediator complex is a central regulator of RNA polymerase II transcription, integrating signals from transcription factors and coordinating pre-initiation complex assembly. Beyond this canonical role, numerous studies have implicated Mediator complex in diverse cellular processes, including RNA processing, DNA repair, and translational control. These observations raise a fundamental question: do such functions reflect an expansion of Mediator activity as a complex, or the emergence of specialized functions at the level of individual subunits? In this review, we examine the ability of Mediator subunits to function independently of their canonical context and discuss the mechanistic principles that enable subunit specialization within multiprotein assemblies.
Small bites for big problems: stepwise aggregate degradation by autophagy.
Hipp MS, Mauthe M
Biochem Soc Trans · 2026 Jun · PMID 42325197 · Full text
Protein aggregates are a pathological hallmark of diverse disorders, including many neurodegenerative diseases, but also cardiometabolic disease and cancer. While the ubiquitin-proteasome system efficiently removes many...
Protein aggregates are a pathological hallmark of diverse disorders, including many neurodegenerative diseases, but also cardiometabolic disease and cancer. While the ubiquitin-proteasome system efficiently removes many soluble misfolded proteins, large or persistent assemblies often require the autophagy-lysosome pathway for their degradation. In the present mini-review, we summarize our knowledge of aggrephagy, the selective clearance of protein aggregates by autophagy, and discuss two recent manuscripts that argue that some aggregates must be primed for autophagosomal degradation, through chaperone-mediated remodeling. Aggrephagy substrates are defined by aggregate architecture, biophysical state, surface accessibility, and the physical constraints of membrane capture. These features help to explain why recruitment of selective autophagy receptors is necessary yet insufficient for clearance. Receptor clustering is required to concentrate early autophagy factors to establish initiation hubs, but successful degradation often requires upstream generation of smaller 'aggrephagy-competent' cargo units, which contain autophagy receptor clusters that successfully initiate autophagosome formation. Recent work supports a model in which larger aggregates are cleared through stepwise degradation enabled by prior remodeling steps that involve p97/VCP-driven disintegration or a chaperone module (DNAJB6-HSP70-HSP110) cooperating with the proteasomal 19S regulatory particle.
Lipid traffic: an enigmatic alliance between ORPs and a TMEM16-like protein at membrane contact sites.
Fabbre A, Drin G
Biochem Soc Trans · 2026 Jun · PMID 42325196 · Full text
Lipid transfer proteins (LTPs) play a critical role in distributing lipids within eukaryotic cells. In yeast, Osh6 and Osh7, which belong to the oxysterol-binding protein-related protein family, transfer phosphatidylseri...
Lipid transfer proteins (LTPs) play a critical role in distributing lipids within eukaryotic cells. In yeast, Osh6 and Osh7, which belong to the oxysterol-binding protein-related protein family, transfer phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) in exchange for phosphatidylinositol 4-phosphate (PI(4)P). These proteins localize at ER-PM contact sites by associating with Ist2, an ER-resident TMEM16-like protein that bridges the ER and PM via a long intrinsically disordered region (IDR). Recent studies have shown that this association ensures accurate PS transfer by concentrating Osh6 and Osh7 at the ER-PM interface while preserving their ability to access both membranes. However, it remains unclear how these LTPs function when bound to the Ist2 IDR, whose length far exceeds the ER-PM distance at contact sites, and why they do not integrate both the tethering and the PS/PI(4)P exchange functions, like their human homologs. Additionally, it has been revealed that Ist2 can transfer lipids across the ER membrane via a scramblase activity. Yet, whether and why this activity is coupled to the PS/PI(4)P exchange activity of Osh6 and Osh7 remains unknown. The Ist2-Osh6/7 system emerges as a fascinating model that integrates tethering, scramblase, and lipid exchange functions. Future studies of this system are likely to provide important insights into how lipid transfer processes are coordinated at membrane contact sites.
Structure and molecular function of the BCL7 proteins.
Martin F, Bergamin E
Biochem Soc Trans · 2026 Jun · PMID 42305078 · Full text
Initially identified through chromosomal translocations in lymphomas, the BCL7 protein family, comprising the three paralogues BCL7A, BCL7B, and BCL7C, has recently emerged as a core component of mammalian SWI/SNF ATP-de...
Initially identified through chromosomal translocations in lymphomas, the BCL7 protein family, comprising the three paralogues BCL7A, BCL7B, and BCL7C, has recently emerged as a core component of mammalian SWI/SNF ATP-dependent chromatin remodeling complexes. Although their functions remained poorly understood for many years, recent structural and biochemical studies have substantially improved our understanding of their roles. Cryo-electron microscopy studies revealed that BCL7 proteins interact with nucleosomes through a conserved N-terminal arginine anchor motif that binds the nucleosomal acidic patch and stabilize the actin-related protein module through a conserved β-hairpin motif. These findings identify BCL7 proteins as structural elements that contribute to nucleosome engagement and SWI/SNF complex integrity. Comparative analyses further suggest that key structural features of BCL7 proteins are conserved across evolution despite limited sequence similarity. In addition to their roles in chromatin remodeling, increasing evidence links BCL7 proteins to hematological malignancies, solid tumors, and developmental disorders, highlighting their emerging value as biomarkers and potential therapeutic targets. This review summarizes current knowledge on the structure, evolution, and functions of the BCL7 family and outlines future directions for elucidating their contribution to chromatin regulation and disease.
The impact of psuedouridine modification on human tRNA.
Stone Y, Morgan E, Su YH … +2 more , Kuo CY, Lin TY
Biochem Soc Trans · 2026 Jun · PMID 42290177 · Full text
Transfer RNA (tRNA) is an important RNA in cells that decodes messenger RNA (mRNA) codons during protein translation to ensure correct amino acid sequences. The biogenesis of tRNA involves multiple processing steps to pr...
Transfer RNA (tRNA) is an important RNA in cells that decodes messenger RNA (mRNA) codons during protein translation to ensure correct amino acid sequences. The biogenesis of tRNA involves multiple processing steps to produce mature and functional molecules. Pseudouridine (Ψ), a derivative of uridine, is an abundant RNA modification and occurs at multiple positions within tRNAs. These modified sites are highly conserved across organisms. Classical biochemical studies have established that Ψ stabilises RNA-RNA interactions, but structural characterisations and molecular dynamics simulations reveal that Ψ can locally remodel tRNA architecture in ways that are dictated by where it is within tRNAs. Advances in transcriptome-wide Ψ mapping have uncovered additional modified sites beyond those previously described, with several novel sites appearing to be regulated in a cellular context-dependent manner. Furthermore, dysregulated pseudouridylation has been implicated in conditions ranging from cancer to inherited genetic disorders. Together, these developments reframe our understanding of Ψ from a well-established RNA stabiliser to a modification with roles far more dynamic, context-dependent, and clinically relevant than previously appreciated. The present review summarises and discusses the up-to-date developments in the impacts of pseudouridylation on human tRNA biogenesis, tRNA functions, and human health. More mechanistic questions remain open and will require further investigation. As pseudouridylation can also happen in mRNA and rRNA, exploring the interplay between these RNAs will be crucial for fundamental biology and advancing Ψ applications in biotechnology and biomedical uses.
Ubiquitin beyond the proteome: lipids, glycans, metabolites, nucleic acids, and an expanding molecular landscape.
Endo A, Yoshida Y
Biochem Soc Trans · 2026 Jun · PMID 42283083 · Full text
Ubiquitination is a versatile post-translational modification process in which the small globular protein ubiquitin is covalently attached to substrate proteins to generate diverse cellular signals. Although originally c...
Ubiquitination is a versatile post-translational modification process in which the small globular protein ubiquitin is covalently attached to substrate proteins to generate diverse cellular signals. Although originally characterized by its role in proteasome-mediated protein degradation, ubiquitination is now recognized as a central regulator of numerous processes, including signaling, trafficking, and immunity. Canonical ubiquitination is mediated by a cascade of E1 (activating), E2 (conjugating), and E3 (ligase) enzymes that repeatedly conjugate ubiquitin molecules to lysine residues on substrate proteins, leading to the formation of polyubiquitin chains with distinct topologies. The modification is reversed by deubiquitinating enzymes. Notably, components of the ubiquitin system comprise approximately 7% of the human proteome, underscoring its importance in biological regulation. Recent advances have revealed the broad scope of ubiquitination. Ubiquitin was found to conjugate not only to lysine but also to serine, threonine, and cysteine, indicating its unexpected chemical flexibility. Furthermore, ubiquitination can be directed toward other post-translational modifications, particularly glycosylation and ADP-ribosylation, highlighting the extensive crosstalk between modification systems. Strikingly, lipids, sugars, metabolites, nucleic acids, and even synthetic small-molecule compounds have been identified as ubiquitinated substrates. The hypothesis that virtually all classes of molecules are targeted by ubiquitination has become increasingly plausible. Taken together, these findings redefine ubiquitination as a far more general modification process than previously appreciated. In this mini-review, we focus on recent progress in non-proteinaceous ubiquitination research, summarize emerging substrate classes, and discuss key challenges in elucidating the underlying mechanisms and physiological roles of this expanding modification landscape.
The multifaceted roles of receptor tyrosine pseudokinases in cellular signalling.
Park EC, Thompson AP, Murphy JM … +2 more , Liang LY, Lucet IS
Biochem Soc Trans · 2026 Jun · PMID 42267535 · Full text
Receptor tyrosine pseudokinases comprise approximately 10% of the receptor tyrosine kinase family and lack phosphotransferase activity due to substitutions of essential catalytic residues within their kinase folds. This...
Receptor tyrosine pseudokinases comprise approximately 10% of the receptor tyrosine kinase family and lack phosphotransferase activity due to substitutions of essential catalytic residues within their kinase folds. This review critically examines the eight human receptor tyrosine pseudokinases: EphA10, EphB6, HER3, PTK7, ROR1, ROR2, RYK, and STYK1. By reconciling recent structural and functional data, we highlight the diverse non-catalytic mechanisms these pseudokinases employ in cellular communication. This comprehensive analysis provides insights into non-canonical signalling pathways and highlights potential for therapeutic opportunities in diseases associated with pseudokinase dysfunction.
Emerging roles of pterins as signaling molecules in bacteria.
Rucker P, Augusta L, Fuqua C … +1 more , Allen KD
Biochem Soc Trans · 2026 Jun · PMID 42253079 · Full text
Pterins are redox-active biomolecules with well-established functions as enzymatic cofactors in all domains of life. Examples of pterin cofactors include tetrahydrofolate, an essential carrier of one-carbon units, and th...
Pterins are redox-active biomolecules with well-established functions as enzymatic cofactors in all domains of life. Examples of pterin cofactors include tetrahydrofolate, an essential carrier of one-carbon units, and the molybdenum cofactor (Moco)-composed of molybdopterin bound to molybdenum or tungsten-which supports a wide range of redox reactions for diverse enzymes. Pterins also play important roles outside of enzyme active sites where they serve as antioxidants and immune system modulators. Recently, a new role for pterins in bacteria has emerged through the discovery of a pterin-dependent regulator called DcpA that modulates the cytoplasmic second messenger cyclic-di-guanylate monophosphate (c-di-GMP) levels and biofilm formation in Agrobacterium tumefaciens, a model bacterial plant pathogen. The regulatory pathway involves the PruA pteridine reductase and a periplasmic pterin-binding protein termed PruR. This review provides an overview of each of the key players in this pathway and highlights the broad distribution of the respective genes that supports the presence of similar pterin-mediated regulatory pathways in diverse bacteria. In our current model for the A. tumefaciens pathway, PruA generates a tetrahydropterin species that is released to the periplasm where it binds to PruR. The pterin-PruR complex then interacts with the periplasmic domain of DcpA to promote c-di-GMP degradation. The decreased levels of cytoplasmic c-di-GMP disfavor attachment and limit biofilm formation. The redox active nature of pterins is likely a central facet of their signaling functions, where the different redox states of a given pterin species may reflect changing environmental conditions.
Fatty acid esters of hydroxy fatty acids and alkyl-diacylglycerols: minor but bioactive components in human milk.
Lee MLX, Elejalde U, Cazenave-Gassiot A
Biochem Soc Trans · 2026 Jun · PMID 42253078 · Full text
As the optimal source of nutrition for infants, investigations into the human milk lipidome have been quite extensive. Much of the work, however, has been focused on major lipid components such as triglycerides, possibly...
As the optimal source of nutrition for infants, investigations into the human milk lipidome have been quite extensive. Much of the work, however, has been focused on major lipid components such as triglycerides, possibly undermining its actual complexity. This review focuses on two minor but bioactive lipid classes in human milk: fatty acid esters of hydroxy fatty acids (FAHFAs) and alkyl-diacylglycerols (TG(O)s). FAHFAs are known to exhibit anti-diabetic and anti-inflammatory effects, while TG(O)s are important for the prevention of childhood obesity. With the knowledge that early nutrition and metabolic health influence the risk of metabolic dysfunctions later in life, a comprehensive understanding of FAHFAs and TG(O)s, along with reliable characterisations in human milk, would better allow for the development of accurate human milk fat substitutes. This could have future implications as alternative or preventive treatments for infants with early markers of metabolic dysfunction, including diabetes and obesity. The structural characteristics, pathways for biosynthesis and degradation, bioactivity, dietary sources, and characterisations of FAHFAs and TG(O)s in human milk are discussed. Their statuses as emerging lipid classes, however, is reflected in the incomplete understanding of their biochemical pathways. Characterisations of FAHFAs and TG(O)s in human milk are relatively poor, and contradicting results are reported. This review also addresses the challenges involved in the study of minor lipids in complex biological matrices, and the possible reasons underlying the slower evolution of our understanding of FAHFAs and TG(O)s in human milk and their associations with health outcomes.
Transcriptomic regulation of pancreatic acinar cell homeostasis and plasticity.
Zhang X, Luo C, Coughlin K … +3 more , Li FQ, Takemaru KI, Wan L
Biochem Soc Trans · 2026 Jun · PMID 42237897 · Full text
Pancreatic acinar cells are highly specialized secretory epithelial cells in which coordinated transcriptional, epigenetic, and post-transcriptional regulatory mechanisms maintain digestive enzyme production, polarized a...
Pancreatic acinar cells are highly specialized secretory epithelial cells in which coordinated transcriptional, epigenetic, and post-transcriptional regulatory mechanisms maintain digestive enzyme production, polarized architecture, and lineage fidelity. This homeostatic network preserves acinar identity while enabling rapid adaptation to physiological stress. Disruption of these regulatory mechanisms triggers acinar-to-ductal metaplasia (ADM), a reversible reprogramming state that supports acinar cell survival and regeneration after acute injury. However, if ADM persists under chronic inflammation or oncogenic KRAS activation, it can facilitate the initiation of pancreatic ductal adenocarcinoma. Elucidating these mechanisms offers opportunities to restore acinar cell homeostasis, reverse ADM, and prevent neoplastic transformation. In this review, we summarize current knowledge on the transcriptional, epigenetic, and post-transcriptional regulation of acinar cell homeostasis and plasticity, with emphasis on their roles in ADM.
The primary cilium at the helm: gatekeeper of TGF-β superfamily signaling in development, homeostasis, and disease.
Herrera-Cid C, Thomsen OK, Désarbre L … +5 more , Marin RB, Doganli C, Pedersen LB, Larsen LA, Christensen ST
Biochem Soc Trans · 2026 Jun · PMID 42233350 · Full text
The transforming growth factor-beta (TGF-β) superfamily is crucial for regulating cell proliferation, differentiation, migration, and tissue homeostasis, and plays a central role in embryonic development and function of...
The transforming growth factor-beta (TGF-β) superfamily is crucial for regulating cell proliferation, differentiation, migration, and tissue homeostasis, and plays a central role in embryonic development and function of tissues and organs. Dysregulation of these pathways contributes to a broad spectrum of diseases, including cancer, fibrosis, and developmental disorders. The present review explores how the primary cilium, a specialized signaling organelle, orchestrates TGF-β superfamily signaling, with a focus on emerging evidence of its role in heart and brain development, as well as in tissue homeostasis.
Insight into the relationship between type IV pilus function and biofilm formation.
Yu Y, Bauer RM, Mahdi R … +1 more , Piepenbrink KH
Biochem Soc Trans · 2026 Jun · PMID 42233349 · Full text
Type IV pili (T4P) are protein nanofibers that can be extended and retracted from the surfaces of many bacterial taxa. They are involved in many aspects of bacterial physiology that differ between bacterial species, incl...
Type IV pili (T4P) are protein nanofibers that can be extended and retracted from the surfaces of many bacterial taxa. They are involved in many aspects of bacterial physiology that differ between bacterial species, including surface motility, DNA uptake, and host-cell adherence, but genetically and structurally distinct type IV pilus systems from distantly related bacterial species have also been found to promote the formation of bacterial biofilms. The molecular mechanisms underpinning the promotion of biofilm remain an area of active investigation and may be both manifold and variable between type IV pilus systems. Two areas of recent interest are interactions between T4P and extracellular DNA and the relationship between surface-adhered biofilms and suspended aggregates. In the present review, we critically discuss the current state of knowledge of type IV pilus function and how these structures may interact with other biomolecules to influence the formation of multicellular bacterial communities. We examine the evidence for how alterations in DNA-binding, pilus retraction, and pilus composition have downstream effects on the formation of bacterial biofilms.
A pore is a pore is a pore (or a hub?): VDAC oligomerization in mitochondrial connectivity and modulation.
De Pinto V, Battiato G, Conti-Nibali S … +1 more , Cubisino SAM
Biochem Soc Trans · 2026 Jun · PMID 42233348 · Full text
For decades, the voltage-dependent anion-selective channel (VDAC), formerly known as the mitochondrial porin, was considered a simple pore enabling nearly free permeability across the outer mitochondrial membrane. This s...
For decades, the voltage-dependent anion-selective channel (VDAC), formerly known as the mitochondrial porin, was considered a simple pore enabling nearly free permeability across the outer mitochondrial membrane. This simplified view has been progressively dismantled through the discovery of three mammalian isoforms (VDAC1, VDAC2, and VDAC3) with the gradual attribution, often serendipitous, of diverse cellular roles beyond passive metabolite exchange. Recent advances in cryo-electron microscopy have catalyzed a breakthrough in VDAC research. Three converging lines of evidence are reshaping our understanding: (a) high-resolution structures of VDAC within its native protein complexes; (b) discovery of unexpected functions, including phospholipid scrambling and regulation of outer membrane permeabilization through higher-order oligomeric assemblies; and (c) structural determination of VDAC interactions with macromolecules, as well as small-molecule modulators. Collectively, these insights have strengthened the consideration of VDAC as a multifunctional signaling hub and therapeutic target, with emerging small molecules and peptides designed to modulate gating, oligomerization, and interfering with interacting partners. The aim of this review is to summarize current structural, functional, and pharmacological advances in VDAC biology, emphasizing how oligomerization dynamics and isoform specificity orchestrate mitochondrial behavior and offering perspectives on therapeutic strategies for diseases driven by mitochondrial dysfunction.
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