International Journal of Biological Macromolecules, Год журнала: 2024, Номер unknown, С. 137668 - 137668
Опубликована: Ноя. 1, 2024
Язык: Английский
Cellular & Molecular Biology Letters, Год журнала: 2024, Номер 29(1)
Опубликована: Фев. 5, 2024
Abstract For decades, lactate has been considered a byproduct of glycolysis. The shuttle hypothesis shifted the paradigm, demonstrating that not only plays important roles in cellular metabolism but also communications, which can transcend compartment barriers and occur within among different cells, tissues organs. Recently, discovery induce novel post-translational modification, named lysine lactylation (Kla), brings forth new avenue to study nonmetabolic functions for lactate, inspired ‘gold rush’ academic commercial interest. Zhang et al. first showed Kla is manifested histones as epigenetic marks, then mounting evidences demonstrated occurs diverse non-histone proteins. widespread faithfully orchestrates numerous biological processes, such transcription, inflammatory responses. Notably, dysregulation touches myriad pathological processes. In this review, we comprehensively reviewed curated existing literature retrieve identified sites on both proteins summarized recent major advances toward its regulatory mechanism. We thoroughly investigated function underlying signaling pathway summarize how regulates various processes normal physiological states. addition, further highlight effects development human diseases including inflammation response, tumorigenesis, cardiovascular nervous system other complex diseases, might potentially contribute deeply understanding interpreting mechanism pathogenicity. Graphical
Язык: Английский
Процитировано
41
Advanced Science, Год журнала: 2025, Номер unknown
Опубликована: Янв. 31, 2025
Colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the application of anti-ferroptosis therapy. Through drug screening, it found that histone deacetylase inhibitor (HDACi) significantly sensitized CRC ferroptosis. The combination HDACi and ferroptosis inducers synergically suppresses growth both in vivo vitro. Mechanically, reduces suppressor protein (FSP1) by promoting its mRNA degradation. Specifically, confirmed specifically targets HDAC1 promotes H3K27ac modification fat mass- obesity-associated gene (FTO) AlkB Homolog 5, RNA Demethylase (ALKBH5), results significant activation FTO ALKBH5. ALKBH5 N6-methyladenosine (m6A) on FSP1 mRNA, leading Crucially, lactylation HDAC1K412 essential for regulation. Both Vorinostat (SAHA) Trichostatin A (TSA) notably diminish comparison other inhibitors, exhibiting a consistent trend increasing susceptibility In conclusion, research reveals decreases sensitize can be promising therapeutic strategy CRC.
Язык: Английский
Процитировано
6
Journal of Clinical Investigation, Год журнала: 2025, Номер 135(1)
Опубликована: Янв. 1, 2025
Posttranslational modification (PTM) of the amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD). Recent evidence reveals that lactylation modification, as novel PTM, is implicated occurrence and development AD. However, whether how APP contributes to both pathogenesis cognitive function AD remains unknown. Here, we observed reduction patients model mice cells. Proteomic mass spectrometry analysis further identified lysine 612 (APP-K612la) crucial site for lactylation, influencing amyloidogenic processing. A lactyl-mimicking mutant (APPK612T) reduced amyloid-β peptide (Aβ) generation slowed down deficits vivo. Mechanistically, APPK612T appeared facilitate trafficking metabolism. lactylated entering endosome inhibited its binding BACE1, suppressing subsequent cleavage. Instead, it promoted interaction between CD2-associated (CD2AP), thereby accelerating endosomal-lysosomal degradation pathway APP. In APP23/PS45 double-transgenic mouse AD, APP-Kla was susceptible L-lactate regulation, which Aβ pathology repaired spatial learning memory deficits. Thus, these findings suggest targeting may be promising therapeutic strategy humans.
Язык: Английский
Процитировано
5
Cell Death Discovery, Год журнала: 2025, Номер 11(1)
Опубликована: Фев. 8, 2025
Abstract Histone lactylation plays a crucial role in cancer progression, but its impact on breast (BC) tumorigenesis is still unclear. We utilized chromatin immunoprecipitation sequencing with H3K18la antibodies, transcriptomics of clinical BC samples, and proteomics ATAC-seq analyses vivo tumors to identify the genes regulated by transcription factor PPARD. qPCR Western blot assays were used detect expressions molecules. discovered that levels higher tissues compared adjacent non-cancerous tissues. promoted expression PPARD, which turn influenced AKT, not ILK. analysis revealed glycolysis cells enhanced accessibility. Additionally, we confirmed HDAC2 HDAC3 act as “erasers” for H3 lysine lactylation. During analysis, AKT-phosphorylation aerobic respiration inhibitor group exhibited an apparent disparity activity. Our study demonstrated changes downstream PPARD support cell survival under anaerobic conditions. accelerated proliferation promoting phosphorylation AKT. This highlights therapeutic potential targeting H3K18la/PPARD/AKT axis cancer, providing new insights into epigenetic regulation metabolism (Trial registration: The was approved Research Ethics Committee Shandong Provincial Third Hospital (KYLL-2023057; https://www.medicalresearch.org.cn/ )).
Язык: Английский
Процитировано
3
Frontiers in Immunology, Год журнала: 2024, Номер 15
Опубликована: Май 8, 2024
Lactic acid was formerly regarded as a byproduct of metabolism. However, extensive investigations into the intricacies cancer development have revealed its significant contributions to tumor growth, migration, and invasion. Post-translational modifications involving lactate been widely observed in histone non-histone proteins, these play crucial role regulating gene expression by covalently attaching lactoyl groups lysine residues proteins. This discovery has greatly enhanced our comprehension lactic acid's involvement disease pathogenesis. In this article, we provide comprehensive review intricate relationship between immunity, occurrence lactylation malignant tumors, exploitation targeted lactate-lactylation immunotherapy. Additionally, discuss future research directions, aiming offer novel insights that could inform investigation, diagnosis, treatment related diseases.
Язык: Английский
Процитировано
18
MedComm, Год журнала: 2024, Номер 5(9)
Опубликована: Сен. 1, 2024
Abstract Cell death regulation is essential for tissue homeostasis and its dysregulation often underlies cancer development. Understanding the different pathways of cell can provide novel therapeutic strategies battling cancer. This review explores several key mechanisms apoptosis, necroptosis, autophagic death, ferroptosis, pyroptosis. The research gap addressed involves a thorough analysis how these be precisely targeted therapy, considering tumor heterogeneity adaptation. It delves into genetic epigenetic factors signaling cascades like phosphatidylinositol 3‐kinase/protein kinase B/mammalian target rapamycin (PI3K/AKT/mTOR) mitogen‐activated protein kinase/extracellular signal‐regulated (MAPK/ERK) pathways, which are critical death. Additionally, interaction microenvironment with cells, particularly influence hypoxia, nutrient deprivation, immune cellular interactions, explored. Emphasizing strategies, this highlights emerging modulators inducers such as B lymphoma 2 (BCL2) homology domain 3 (BH3) mimetics, tumour necrosis factor‐related apoptosis‐inducing ligand (TRAIL), chloroquine, innovative approaches to induce ferroptosis provides insights therapy's future direction, focusing on multifaceted circumvent drug resistance. examination evolving underlines considerable clinical potential continuous necessity in‐depth exploration within scientific domain.
Язык: Английский
Процитировано
15
Genes & Development, Год журнала: 2024, Номер 38(11-12), С. 473 - 503
Опубликована: Июнь 1, 2024
The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers innovative combination therapies can be used to address challenging difficult treat disease states. This review highlights key writers, remodelers control, as well their connection with states recent advances in associated therapies.
Язык: Английский
Процитировано
10
Frontiers in Immunology, Год журнала: 2025, Номер 16
Опубликована: Март 26, 2025
Lactate has emerged as a key regulator in the tumor microenvironment (TME), influencing both progression and immune dynamics. As byproduct of aerobic glycolysis, lactate satisfies metabolic needs proliferating cells while reshaping TME to facilitate evasion. Elevated levels inhibit effector such CD8 + T natural killer cells, supporting immunosuppressive regulatory myeloid-derived suppressor thus fostering an environment. promotes epigenetic reprogramming, stabilizes hypoxia-inducible factor-1α, activates nuclear factor kappa B, leading further immunological dysfunction. In this review, we examined role suppression, treatment resistance. We also discuss promising therapeutic strategies targeting metabolism, including dehydrogenase inhibitors, monocarboxylate transporter neutralization methods, all which can restore function enhance immunotherapy outcomes. By highlighting recent advances, review provides theoretical foundation for integrating lactate-targeted therapies into clinical practice. highlight potential synergy between these current immunotherapeutic strategies, providing new avenues addressing TME-related challenges improving outcomes patients with cancer.
Язык: Английский
Процитировано
2
Nature Cell Biology, Год журнала: 2025, Номер unknown
Опубликована: Апрель 4, 2025
Язык: Английский
Процитировано
2
EBioMedicine, Год журнала: 2024, Номер 111, С. 105502 - 105502
Опубликована: Дек. 10, 2024
Язык: Английский
Процитировано
8