bims-cemest Biomed News
on Cell metabolism and stress
Issue of 2025–07–06
sixteen papers selected by
Jessica Rosarda, Uniformed Services University
  1. Failed Cellular Surveillance Enables Pathogenic Matrix Deposition in a COL2A1-Related Osteoarthritis.
  2. Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.
  3. Unveiling roles of NGLY1 in cellular homeostasis and related diseases.
  4. The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.
  5. Ceramide homeostasis in hepatic lipid droplets.
  6. A privileged ER compartment for posttranslational heteromeric assembly of an ion channel.
  7. TUG protein acts through a disordered region to organize the early secretory pathway.
  8. Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
  9. Mechanism of nascent chain removal by the ribosome-associated quality control complex.
  10. Chemoproteomics identifies protein ligands for monoacylglycerol lipids.
  11. Small-molecule probes for imaging and impairing the Golgi apparatus in cancer.
  12. Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
  13. Biotinylated Hsp90β-selective inhibitors.
  14. Molecular machineries and pathways of mitochondrial protein transport.
  15. Site-resolved assessment of targeted protein degradation.
  16. Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.
  1. J Biol Chem. 2025 Jun 30. pii: S0021-9258(25)02286-0. [Epub ahead of print] 110436
    Failed Cellular Surveillance Enables Pathogenic Matrix Deposition in a COL2A1-Related Osteoarthritis.
    Kathryn M Yammine, Sophia Mirda Abularach, Michael Xiong, Seo-Yeon Kim, Agata A Bikovtseva, Vincent L Butty, Richard P Schiavoni, John F Bateman, Shireen R Lamandé, Matthew D Shoulders.
      Mutations in the COL2A1 gene, encoding procollagen-II, cause various chondrodysplasias, including precocious osteoarthritis with mild spondyloepiphyseal dysplasia engendered by the p.Arg719Cys substitution. The molecular mechanisms underlying these disorders remain incompletely understood, largely owing to the absence of models faithfully recapitulating the human disease. Here, we developed an in vitro human cartilage model using isogenic induced pluripotent stem cell (iPSC) lines carrying either wild-type or Arg719Cys COL2A1. Directed differentiation into chondrocytes yielded cartilage tissues that were analyzed by immunohistochemistry, electron microscopy, SDS-PAGE, and RNA-sequencing. Tissues derived from Arg719Cys heterozygotes displayed a deficient matrix, closely reflecting the human disease phenotype. Arg719Cys procollagen-II was excessively post-translationally modified and partially retained within the endoplasmic reticulum (ER), leading to ER distention. Notably, despite introduction of an aberrant cysteine residue-expected to engage redox-sensitive folding and quality control pathways-Arg719Cys procollagen-II was not detectably recognized by the ER proteostasis network. The resulting inability to mount a quality control response, including activation of the unfolded protein response, indicates a failure in cellular surveillance. As a result, malformed procollagen-II both accumulates intracellularly and is secreted, contributing to the deposition of a structurally compromised extracellular matrix that drives disease pathology. The iPSC-derived cartilage model presented here provides a genetically defined and expandable, human-based system for dissecting the mechanisms of failed proteostasis in collagenopathies. These findings shed light on the types of substitutions in procollagen that cells can or cannot recognize, and underscore the therapeutic potential of targeting cellular surveillance and collagen quality control pathways in COL2A1-related disorders and beyond.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110436
  2. Life Sci Alliance. 2025 Sep;pii: e202403195. [Epub ahead of print]8(9):
    Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.
    Emmanuelle Abgueguen, Massimo Tortarolo, Laura Rouviere, Stefania Marcuzzo, Laura Camporeale, Alexandre Henriques, Laura Pasetto, Georgia R Culley, Valentina Bonetto, Anca Marian, Beatrice L Lejeune, Anne Visbecq, Giuseppe Lauria, Edor Kabashi, Noëlle Callizot, Caterina Bendotti, Pierre Y Miniou.
      A pathological hallmark of ALS is the abnormal accumulation of misfolded proteins (e.g., TDP-43) and enlarged endoplasmic reticulum (ER), indicating ER stress. To resolve this stress, cells initiate the Unfolded Protein Response (UPR). However, unresolved stress leads to apoptosis. In ALS, UPR activation fails to resolve proteostasis impairment. UPR activation modulators, among them Sephin1, reduce protein aggregates and improve motor neuron survival in ALS models. We demonstrate that following glutamate intoxication, Sephin1 increases motor neuron survival by reducing mitochondria ROS production and extranuclear TDP-43. Sephin1 reduces abnormal splicing because of TDP-43 nuclear loss of function following oxidative stress. In SOD1G93A mice, Sephin1 treatment decreases TDP-43 in triton-insoluble fraction, improving motor neuron survival in spinal cord. Sephin1 improves motor neurons survival, motor function and survival of mutated TDP-43 transgenic zebrafish. Sephin1 improves motor neuron survival in ALS models by reducing TDP-43 cytoplasmic mislocalization and its toxicity. These findings open new therapeutic opportunities for Sephin1 in neurodegenerative pathologies with TDP-43 proteinopathy, including ALS.
    DOI:  https://doi.org/10.26508/lsa.202403195
  3. Cell Signal. 2025 Jun 30. pii: S0898-6568(25)00386-9. [Epub ahead of print]134 111971
    Unveiling roles of NGLY1 in cellular homeostasis and related diseases.
    Chenxi Zhan, Xuye Zhao, Yaoxin Wei, Renqiang Yang, Nianlong Yan.
      NGLY1, a cytoplasmic enzyme, removes N-glycans from misfolded glycoproteins during endoplasmic reticulum-associated degradation (ERAD), a critical protein quality control mechanism. ERAD coordinates with the ubiquitin-proteasome system (UPS), working synergistically to maintain cellular proteostasis and mitigate protein toxicity. Emerging evidence highlights the multifaceted roles of NGLY1 in proteostasis activity, autophagy, endoplasmic reticulum stress, and related areas, all of which are connected to numerous diseases, including neurodegenerative disorders and cancer, among others. To fully understand the function of NGLY1 in cellular homeostasis, this review comprehensively discusses recent research progress and the related molecular mechanisms of NGLY1 in cellular homeostasis and associated diseases, as well as the therapeutic approaches.
    Keywords:  Cellular homeostasis; ERAD; NFE2L1; NGLY1
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111971
  4. Cell Death Dis. 2025 Jul 05. 16(1): 494
    The role of cardiolipin in mitochondrial dynamics and quality control in neuronal ischemia/reperfusion injury.
    Katlynn J Emaus, Garrett M Fogo, Joseph M Wider, Thomas H Sanderson.
      Stroke and cardiac arrest claim the lives of millions worldwide each year emphasizing the importance of understanding this injury cascade. These pathologies present as a 'two hit' injury termed ischemia/reperfusion (I/R) injury. The primary injury is the initial disruption of blood flow and ischemic state while the secondary injury, paradoxically, being the return of blood flow and oxygen availability. The injury caused by reperfusion presents a viable window for therapeutic intervention, stressing the importance of understanding this injury pathology. Constantly undergoing fission and fusion, mitochondria are dynamic organelles that play a vital role in maintaining cell health and are highly susceptible to I/R injury. Following I/R injury, disrupted mitochondrial dynamics and quality control ultimately lead to a dysfunctional mitochondrial network, energy depletion and eventually cell death. While mitochondrial dynamics and quality control have been studied extensively in the realm of I/R injuries, the role of mitochondrial lipids is emerging as an important component of injury progression. The inner mitochondrial membrane lipid, cardiolipin has been demonstrated to play an integral role in maintaining mitochondrial quality control, dynamics and energy production. In response to oxidative stress, cardiolipin has been shown to interact with several important proteins involved in mitochondrial dynamics while also contributing to integral signaling cascades. This review will highlight the role of cardiolipin in mitochondrial dynamics and quality control in response to neuronal I/R injury.
    DOI:  https://doi.org/10.1038/s41419-025-07786-8
  5. Biochem Soc Trans. 2025 Apr 18. 53(2): 509-518
    Ceramide homeostasis in hepatic lipid droplets.
    Leobarda Robles-Martinez, Kylie H Morin, Mariana Nikolova-Karakashian.
      Almost all eukaryotic cells have the capacity to form lipid droplets (LDs) in conditions of excess energy. Traditionally thought to be just inert fat reservoirs, LDs have recently emerged as important metabolic regulators of cellular stress response that buffer excess free fats and protect cells from lipotoxicity. Ceramide is a bioactive lipid that accumulates in metabolic tissues during fat oversupply. Emerging evidence suggests that sphingolipids and sphingolipid-metabolizing enzymes are found in the LDs and affect LD biogenesis and functions. This article aims to summarize the evidence, delineate some plausible functions of ceramide in hepatic LD biogenesis, and illustrate some of the challenges in this novel field of research. We focus on the biogenesis of LDs in hepatocytes, the parenchymal cells of the liver, because non-alcoholic fatty liver disease is the quintessential manifestation of metabolic stress caused by fat oversupply.
    Keywords:  biogenesis; ceramide; lipid droplets; mitochondria; steatosis
    DOI:  https://doi.org/10.1042/BST20253042
  6. Proc Natl Acad Sci U S A. 2025 Jul 08. 122(27): e2500218122
    A privileged ER compartment for posttranslational heteromeric assembly of an ion channel.
    Sudharsan Kannan, William Kasberg, Liliana R Ernandez, Anjon Audhya, Gail A Robertson.
      Mechanisms underlying heterotypic subunit assembly of ion channels and other oligomeric complexes are poorly understood. In the human heart, heteromeric assembly of two isoforms encoded by the human ether-à-go-go related gene (hERG) is essential for the normal function of cardiac IKr in ventricular repolarization, with loss of hERG1b contributing to arrhythmias associated with long QT-syndrome (LQTS). While hERG1a homomers traffic efficiently to the plasma membrane, hERG1b homomers are retained in the endoplasmic reticulum (ER). When expressed together, the two subunits avidly associate during biogenesis. Seeking rules specifying heteromeric association, we characterized the fate of hERG1b proteins using confocal and superresolution imaging in fixed and live HeLa cells. We found hERG1b sequestered in punctate intracellular structures when expressed alone in HeLa cells. These puncta, which depend on the presence of an N-terminal "RXR" ER retention signal, represent a privileged ER subcompartment distinct from that containing ER-retained, type 2 (hERG-based) LQTS mutant proteins, which were rapidly degraded by the proteasome. Introducing hERG1a to cells with preformed hERG1b puncta dissolved these puncta by rescuing extant hERG1b. Rescue occurred by association of fully translated hERG1b with 1a, a surprising finding given previous studies demonstrating cotranslational heteromeric association. We propose that sequestration limits potentially deleterious surface expression of hERG1b homomeric channels while preserving hERG1b for an alternative mode of heteromeric hERG1a/1b channel assembly posttranslationally. These findings reveal a surprising versatility of biosynthetic pathways promoting heteromeric assembly.
    Keywords:  arrhythmia; condensate; hERG; long QT syndrome; protein trafficking
    DOI:  https://doi.org/10.1073/pnas.2500218122
  7. Nat Commun. 2025 Jul 01. 16(1): 5518
    TUG protein acts through a disordered region to organize the early secretory pathway.
    Anup Parchure, Helen Tejada, Zhiqun Xi, Yeongho Kim, Maohan Su, You Yan, Omar Julca-Zevallos, Abel R Alcázar-Román, Marie Villemeur, Xinran Liu, Derek Toomre, Ishier Raote, Jonathan S Bogan.
      The Endoplasmic Reticulum (ER)-Golgi Intermediate Compartment (ERGIC) is a network of tubules and vesicles known for producing COPI vesicles and receiving COPII vesicles from the ER. Much about its identity, stability, and regulation remains unknown. Here, we show that TUG (UBXN9, Aspscr1) protein, a central regulator of GLUT4 trafficking, localizes to the ERGIC, and that its deletion enhances anterograde flux of a model soluble cargo protein. TUG deletion redistributes ERGIC markers to the cis-Golgi and alters Golgi morphology. TUG forms biomolecular condensates in vitro and contains a central disordered region that mediates its recruitment to ERGIC membranes. A distinct N-terminal region mediates its oligomerization in cells. TUG deletion disrupts ERGIC-dependent processes, including autophagy and collagen secretion, and alters the targeting of the CFTR chloride channel. We conclude that TUG organizes and stabilizes ERGIC membranes to support their roles in diverse secretory and degradative membrane trafficking pathways.
    DOI:  https://doi.org/10.1038/s41467-025-60691-8
  8. Nat Commun. 2025 Jul 01. 16(1): 5465
    Mitophagy mitigates mitochondrial fatty acid β-oxidation deficient cardiomyopathy.
    Nuo Sun, Hayley Barta, Samhita Chaudhuri, Kangxuan Chen, Jiacheng Jin, Hongke Luo, Mingchong Yang, Judith Krigman, Ruohan Zhang, Shridhar Sanghvi, Shiori Sekine, Hannah Sanders, Dominic Kolonay, Mudra Patel, Kedryn Baskin, Harpreet Singh, Pengyi Zhang, Gang Xin, Toren Finkel.
      The healthy heart relies on mitochondrial fatty acid β-oxidation (FAO) to sustain its high energy demands. FAO deficiencies can cause muscle weakness, cardiomyopathy, and, in severe cases, neonatal/infantile mortality. Although FAO deficits are thought to induce mitochondrial stress and activate mitophagy, a quality control mechanism that eliminates damaged mitochondria, the mechanistic link in the heart remains unclear. Here we show that mitophagy is unexpectedly suppressed in FAO-deficient hearts despite pronounced mitochondrial stress, using a cardiomyocyte-specific carnitine palmitoyltransferase 2 (CPT2) knockout model. Multi-omics profiling reveals impaired PINK1/Parkin signaling and dysregulation of PARL, a mitochondrial protease essential for PINK1 processing. Strikingly, deletion of USP30, a mitochondrial deubiquitinase that antagonizes PINK1/Parkin function, restores mitophagy, improves cardiac function, and significantly extends survival in FAO-deficient animals. These findings redefine the mitophagy response in FAO-deficient hearts and establish USP30 as a promising therapeutic target for metabolic cardiomyopathies and broader heart failure characterized by impaired FAO.
    DOI:  https://doi.org/10.1038/s41467-025-60670-z
  9. Nat Commun. 2025 Jul 01. 16(1): 5792
    Mechanism of nascent chain removal by the ribosome-associated quality control complex.
    Wenyan Li, Talia Scheel, Peter S Shen.
      Errors during translation can cause ribosome stalling, leaving incomplete nascent chains attached to large ribosomal subunits. Cells rely on the Ribosome-associated Quality Control (RQC) complex to recognize, process, and remove these aberrant proteins to maintain proteostasis. Despite its importance, the mechanisms by which the RQC orchestrates nascent chain processing and extraction have remained unclear. Here, we present a cryo-EM structure of the RQC complex from budding yeast, revealing how its core components function in nascent chain removal. We show that the Cdc48 ATPase and its Ufd1-Npl4 adaptor are recruited by the Ltn1 E3 ubiquitin ligase to extract ubiquitylated peptides from the 60S ribosome. Additionally, we find that Rqc1 bridges the 60S subunit with ubiquitin and Ltn1, facilitating formation of K48-linked polyubiquitin chains. These findings provide a structural and mechanistic framework for understanding how the RQC complex collaborates to clear stalled translation products, advancing insight into cellular protein quality control.
    DOI:  https://doi.org/10.1038/s41467-025-61235-w
  10. Commun Chem. 2025 Jul 04. 8(1): 197
    Chemoproteomics identifies protein ligands for monoacylglycerol lipids.
    Karthik Shanbhag, Amol B Mhetre, Ojal Saharan, Archit Devarajan, Anisha Rai, M S Madhusudhan, Harinath Chakrapani, Siddhesh S Kamat.
      Signaling lipids are important hormone-like biomolecules that regulate many physiological processes in humans. However, a significant number of them still remain poorly characterized, despite their direct association to human diseases. While the signaling pathways regulated by the endocannabinoid 2-arachidonoyl-glycerol in mammals are extensively characterized, the same cannot be said about other members of the monoacylglycerol (MAG) family of signaling lipids. Here, we report the synthesis of a bifunctional MAG probe, containing a photoreactive group and an alkyne handle. Using established chemoproteomics approaches coupled to bioorthogonal chemistry, we profile this bifunctional MAG probe in mouse brain and mammalian cell proteomes, and identify hitherto unknown protein ligands for MAG lipids. Finally, we find that the neuronal calcium sensor Hippocalcin is indeed a putative MAG protein ligand, and show that MAG lipids may have a role to play in calcium sensing and downstream signaling in the mammalian brain.
    DOI:  https://doi.org/10.1038/s42004-025-01589-w
  11. RSC Med Chem. 2025 Jun 16.
    Small-molecule probes for imaging and impairing the Golgi apparatus in cancer.
    Phanindra Kumar, Poulomi Sengupta, Sudipta Basu.
      The Golgi apparatus (GA) is one of the most important subcellular organelles controlling protein processing, post-translational modification and secretion. Dysregulation of the GA structure and function leads to multiple pathological states, including cancer development and metastasis. Consequently, visualizing GA dynamic structures and their impairment in cancer has emerged as a novel strategy for next-generation unorthodox cancer therapeutics. However, the major challenge in GA-mediated theranostic probe development is the specific targeting of the GA within the subcellular milieu due to the lack of GA-recognizing chemical entities. In this review, we delineated various chemical functionalities that are extensively used as GA-homing moieties. Moreover, we outlined GA imaging probes consisting of classical fluorophores as well as novel aggregation-induced emissive (AIE) probes tagged with GA-homing moieties. Furthermore, we described GA-impairing molecules that can damage GA morphology through chemotherapeutic and photodynamic therapy (PDT) in cancer. Finally, we addressed the current challenges in this emerging and underexplored field of GA-targeted theranostics and proposed potential solutions to guide future cancer therapeutics.
    DOI:  https://doi.org/10.1039/d5md00320b
  12. Nat Commun. 2025 Jul 01. 16(1): 5850
    Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.
    Aliyah Habashy, Christopher Acree, Keun-Young Kim, Ali Zahraei, Martin Dufresne, Sebastien Phan, Melanie Cutler, Emilee Patterson, Alexandra G Mulligan, Kristopher Burkewitz, Charles Robert Flynn, Louise Lantier, Thomas Deerinck, Owen P McGuinness, Jeffrey M Spraggins, Mark H Ellisman, Rafael Arrojo E Drigo.
      Metabolic homeostasis requires engagement of catabolic and anabolic pathways consuming nutrients that generate and consume energy and biomass. Our current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation, and that fail to reveal the spatial characteristics of cell metabolism, and how these aspects relate to the location of cells and organelles within tissue microenvironments. Here we show the application of multi-scale microscopy, machine learning-based image segmentation, and spatial analysis tools to quantitatively map the fate of nutrient-derived 13C atoms across spatiotemporal scales. This approach reveals the cellular and organellar features underlying the spatial pattern of glucose 13C flux in hepatocytes in situ, including the timeline of mitochondria-ER contact dynamics in response to changes in blood glucose levels, and the discovery of the ultrastructural relationship between glycogenesis and lipid droplets.
    DOI:  https://doi.org/10.1038/s41467-025-60994-w
  13. Bioorg Med Chem Lett. 2025 Jul 01. pii: S0960-894X(25)00232-X. [Epub ahead of print] 130323
    Biotinylated Hsp90β-selective inhibitors.
    Chaitanya Kondam, Nitin Sharma, Gaya K Amarasinge, Brian S J Blagg.
      Heat shock protein 90 (Hsp90) has emerged as an attractive target for development of therapeutics against cancer due to its crucial role in folding, stabilization of client proteins associated with oncogenesis. Hsp90 pan inhibitors entered clinical trials for treatment of cancer showed detrimental adverse effects. Hsp90α isoform inhibition has been attributed to on-target toxicity such as cardio- and ocular-toxicity. To determine any off-target toxicities caused by the interaction of Hsp90β inhibitors with other cellular proteins, biotinylated Hsp90β-selective inhibitors with various tether lengths were synthesized and validated in vitro and will be used in affinity purification experiments to identify proteins that interact with Hsp90β-selective inhibitors. These studies will lead to the development of Hsp90β-selective inhibitors with reduced off target toxicity.
    Keywords:  Biotinylated inhibitors; Cancer; Heat shock protein 90 (Hsp90); Hsp90-β isoform; Off-target toxicity
    DOI:  https://doi.org/10.1016/j.bmcl.2025.130323
  14. Nat Rev Mol Cell Biol. 2025 Jul 03.
    Molecular machineries and pathways of mitochondrial protein transport.
    Toshiya Endo, Nils Wiedemann.
      Mitochondria contain about 1,000-1,500 different proteins, most of which are encoded by the nuclear genome and synthesized in the cytosol, although a handful are specified by the mitochondrial DNA and translated within mitochondria. The coordinated transport of nucleus-encoded proteins into mitochondria, followed by their proper folding, assembly and/or integration into mitochondrial membranes, is central to mitochondrial biogenesis. In this Review, we describe the pathways and machineries for protein transport across and insertion into the inner and outer mitochondrial membranes, as well as the targeting and sorting signals, and energy requirements for these processes. These machineries include the TOM and SAM complexes in the outer membrane and the TIM complexes in the inner membrane, and some components in the intermembrane space. We emphasize recent developments in our understanding of the protein structures of the transport machineries and discuss mechanisms for the shift of protein localization and correction of mislocalization.
    DOI:  https://doi.org/10.1038/s41580-025-00865-w
  15. Cell Chem Biol. 2025 Jul 02. pii: S2451-9456(25)00197-7. [Epub ahead of print]
    Site-resolved assessment of targeted protein degradation.
    Ricardo Moreno-Ballesteros, Thomas Pembridge, Gaurav Beniwal, Satpal Virdee.
      Induced proximity using small molecules, exemplified by targeted protein degradation (TPD), represents a highly promising therapeutic strategy with significant untapped potential. However, evaluating an induced proximity event that accurately reflects drug binding typically requires the challenging and costly development of specific ligands, which limits the advancement of medicines based on this modality. To overcome this bottleneck, we combine genetic code expansion with ultra-fast bioorthogonal chemistry to sensitize specific protein sites at single-residue resolution to a generic bioorthogonal proximity inducer (BPI) molecule. Mammalian cells expressing sensitized mutants of the ubiquitin E3 ligases VHL and CRBN exhibit neosubstrate degradation in the presence of a BPI equipped with a ligand targeting bromodomain and extraterminal (BET) proteins. Furthermore, we demonstrate E3-independent degradation through recruitment of an upstream E2 conjugating enzyme. We anticipate that this approach will have broad applicability, enabling comprehensive assessment of the scope of induced proximity.
    Keywords:  E2 conjugating enzymes; E3 ligases; PROTAC; bioorthogonal chemistry; degrader; genetic code expansion; glues; induced proximity; targeted protein degradation; ubiquitin
    DOI:  https://doi.org/10.1016/j.chembiol.2025.06.002
  16. Cell Commun Signal. 2025 Jul 01. 23(1): 311
    Protein post-translational modifications in serine synthetic pathway: functions and molecular mechanisms.
    Mincong Shu, Yuhan Liu, Jianbin Wang.
      Serine is a non-essential amino acid, serving as a precursor for other amino acids, lipids, and nucleotide synthesis. Its supply is ensured by two main mechanisms: exogenous uptake and endogenous synthesis. The serine synthesis pathway (SSP) connects glycolysis with the one-carbon cycle and plays an important role in cellular homeostasis by regulating substance synthesis, redox homeostasis, and gene expression. The de novo SSP involves three successive enzymatic reactions catalyzed by phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH). Post-translational modifications (PTMs), as essential regulatory mechanisms of proteins, play pivotal roles in physiological and pathological processes. This review focuses on the regulatory mode of PTMs on PHGDH, PSAT1, and PSPH, including phosphorylation, ubiquitination, acetylation, methylation, S-palmitoylation, S-nitrosylation, deamidation, SUMOylation, and lactylation. We summarize how these PTMs participate in the metabolic reprogramming of SSP. It helps us better understand the molecular mechanisms and physiological significance of the PTM network in serine synthetic metabolism, providing guidance for subsequent research and development in the future.
    Keywords:  PHGDH; PSAT1; PSPH; Post-translational modification; Serine synthetic pathway
    DOI:  https://doi.org/10.1186/s12964-025-02327-4
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