bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–09–14
six papers selected by
Bruna Martins Garcia, CABIMER
  1. Post-translational modifications at the crossroads of cancer metabolism and immune regulation: therapeutic opportunities and challenges.
  2. LncRNA BASP1-AS1 Drives PCBP2 K115 Lactylation to Suppress Ferroptosis and Confer Oxaliplatin Resistance in Gastric Cancer.
  3. Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.
  4. The role of protein glycosylation in colorectal cancer: From molecular pathways to clinical applications.
  5. Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism.
  6. Hypoxia Aggravates Myocardial Ischemia/Reperfusion Injury Through the Promotion of Ferroptosis via ACSL4 Lactylation.
  1. Int J Surg. 2025 Sep 09.
    Post-translational modifications at the crossroads of cancer metabolism and immune regulation: therapeutic opportunities and challenges.
    Jiahua Liu, Jiaao Sun, Chengming Li, Xiu Shan, Yue Feng, Guangzhen Wu.
      Post-translational modifications (PTMs) are chemical modifications that occur on specific amino acid residues after protein biosynthesis, which can affect protein function by altering protein structure, localization and activity, thus expanding protein diversity. Extensive research has demonstrated that PTMs can regulate various metabolic processes, such as glucose and lipid metabolism, as well as immune modulation in tumor cells, thereby promoting tumor initiation, progression, and metastasis. In this article, we systematically review a class of emerging PTMs whose roles in tumor metabolism and immune regulation have gradually been recognized in recent years, including six types: lactylation, palmitoylation, SUMOylation, succinylation, crotonylation, and myristoylation. First, we summarized the occurrence process and biological behavior of these six PTMs. Next, we elaborate the relationship between these PTMs and tumorigenesis and progression from the perspectives of metabolism and immune regulation of tumor cells. Finally, we summarize recent research progress in targeting these six types of PTMs for cancer therapy. This paper aims to provide directions for related researchers, and to provide a theoretical basis for targeting PTMs to treat tumors and make it possible.
    Keywords:  cancer; glycolysis; immune regulation; lipid metabolism; post-translational modifications; tumor cell metabolism
    DOI:  https://doi.org/10.1097/JS9.0000000000003381
  2. Free Radic Biol Med. 2025 Sep 04. pii: S0891-5849(25)00950-5. [Epub ahead of print]
    LncRNA BASP1-AS1 Drives PCBP2 K115 Lactylation to Suppress Ferroptosis and Confer Oxaliplatin Resistance in Gastric Cancer.
    Yupeng Zhao, Wentao Liu, Kaiyuan Deng, Yunqin Chen, Peng Zhou, Congxing Liu, Guangqing Jiang, Junjie Wu, Yihong Zhang, Huiheng Qu, Bingya Liu, Beiqin Yu, Xin Shi, Jiazeng Xia.
      In oxaliplatin-resistant gastric cancer (GC), multi-omics profiling combined with organoid libraries reveals altered metabolic pathways associated with chemoresistance. We identify a novel lactylation modification at K115 of Poly(RC)-binding protein 2 (PCBP2K115la), which confers functional oxaliplatin resistance. Mechanistic studies demonstrate that the long non-coding RNA BASP1-AS1 assembles a complex containing Unc-51 Like Autophagy Activating Kinase 1 (ULK1) and lactate dehydrogenase A (LDHA), thereby activating LDHA enzymatic activity to increase lactate production. Elevated lactate triggers PCBP2K115la modification, disrupting PCBP2-ARIH2 interaction to inhibit ubiquitin-dependent degradation and stabilize PCBP2. Concurrently, BASP1-AS1-mediated histone H3K14 lactylation transcriptionally upregulates both LDHA and PCBP2, generating a self-amplifying metabolic-epigenetic circuit. This axis critically suppresses ferroptosis and maintains chemoresistance, providing actionable targets for overcoming oxaliplatin resistance in GC.
    Keywords:  Gastric cancer; H3K14la; Lactylation; Oxaliplatin resistance; PCBP2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.002
  3. Sci Adv. 2025 Sep 12. 11(37): eadx6489
    Metabolism-driven posttranslational modifications and immune regulation: Emerging targets for immunotherapy.
    Gujie Wu, Xiaofei Fan, Lin Cheng, Zongwei Chen, Yanjun Yi, Jiaqi Liang, Xiaolong Huang, Na Yang, Jiacheng Yin, Weigang Guo, Yiwei Huang, Shanye Yin.
      The interplay between cellular metabolism and immune regulation is central to immune function and disease progression, revealing notable therapeutic opportunities. Upon activation, immune cells undergo metabolic reprogramming to meet heightened demands for energy and biosynthesis, reshaping regulatory networks across epigenomic, transcriptomic, and proteomic layers. Metabolite-derived posttranslational modifications (PTMs) serve as pivotal mechanisms integrating metabolic intermediates with immune signaling pathways. Beyond classical acetylation, diverse nonacetyl PTMs-including lactylation, succinylation, malonylation, palmitoylation, and myristoylation-modify histone and nonhistone proteins, regulating gene expression, protein stability, subcellular localization, enzymatic activity, and protein-protein interactions. Advances in mass spectrometry and bioinformatics now enable precise characterization of these PTMs, uncovering their broad roles in immune regulation. This review summarizes current progress in immunometabolism and explores future directions such as mechanistic studies, combination strategies, and clinical applications. Metabolite-driven PTMs critically connect metabolism to immune regulation, suggesting promising therapeutic approaches for cancer, autoimmune disorders, and inflammatory diseases.
    DOI:  https://doi.org/10.1126/sciadv.adx6489
  4. Biochim Biophys Acta Rev Cancer. 2025 Sep 08. pii: S0304-419X(25)00180-5. [Epub ahead of print]1880(5): 189438
    The role of protein glycosylation in colorectal cancer: From molecular pathways to clinical applications.
    Tiangui Wu, Jianguo Gu, Yuhan Sun, Pengfei Ye.
      Glycosylation, a pivotal post-translational modification, critically influences colorectal cancer (CRC) progression via dysregulated N- and O-linked pathways, characterized by oligomannose, fucosylation, hypersialylation, truncated O-glycans (Tn, sialyl-Tn), branched N-glycans, and Lewis antigens. These alterations promote tumor aggressiveness, immune evasion, and metastasis through glycoprotein remodeling (e.g., mucins, integrins) and dysregulating glycosyltransferases (such as Fut2, ST6GAL1). Clinically, tumor-associated glycans offer diagnostic potential, with glycomic profiling enhancing early detection. Glycosylation further orchestrates the CRC microenvironment by modulating interactions among tumor cells, microbiota, and immune components. This review focuses exclusively on protein-centric glycosylation and highlights current studies on the roles of glycosylation in CRC, encompassing molecular mechanisms, diagnostic biomarkers, and emerging therapeutic strategies targeting glycosylation enzymes or glycan epitopes. Understanding glycan dysregulation provides new perspectives for biomarker development and targeted interventions in precision oncology.
    Keywords:  Cancer therapy; Colorectal cancer; Glycosylation; Glycosyltransferases; Tumor biomarkers
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189438
  5. Elife. 2025 Sep 08. pii: RP104138. [Epub ahead of print]14
    Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism.
    Mengyun Li, Huan Jin, Yongxiang Liu, Zining Wang, Lin Li, Tiantian Wang, Xiaojuan Wang, Hongxia Zhang, Bitao Huo, Tiantian Yu, Shoujie Wang, Wei Zhao, Jinyun Liu, Peng Huang, Jun Cui, Xiaojun Xia.
      Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by β-glucan. ATAC-seq and RNA-seq analysis reveal that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF, and NF-κB pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf. Additionally, the tumor inhibition effect of β-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM levels through the mTOR-FOXO3-GNMT axis.
    Keywords:  Aurora kinase A; FOXO3; GNMT; S-adenosylmethionine; epigenetics; immunology; inflammation; mouse; trained immunity
    DOI:  https://doi.org/10.7554/eLife.104138
  6. J Cardiovasc Transl Res. 2025 Sep 08.
    Hypoxia Aggravates Myocardial Ischemia/Reperfusion Injury Through the Promotion of Ferroptosis via ACSL4 Lactylation.
    Jiannan Lv, Mingnan Yin, Hongwen Jin.
      Myocardial ischemia/reperfusion injury (MIRI) worsens ischemic damage, with ferroptosis as a key mediator of this iron-dependent cell death. Lactylation, a novel epigenetic modification, remains poorly understood in MIRI-associated ferroptosis. This study aimed to elucidate the mechanistic link between lactylation and ferroptosis in MIRI. Experimental results demonstrated that hypoxia/reoxygenation (H/R) induction combined with lactate (LA) treatment significantly enhanced the protein expression levels, lactylation status, and protein stability of acyl-CoA synthetase long-chain family member 4 (ACSL4). Site-specific analysis identified lysine 83 (K83) as the critical lactylation modification site on ACSL4. Functional studies revealed that LDHA knockdown-mediated suppression of lactate levels attenuated ferroptosis in H/R-treated cells, an effect that was reversed by ACSL4 overexpression. In vivo validation confirmed that LDHA depletion ameliorated ferroptosis-related damage and mitigated MIRI-induced cardiac dysfunction. Collectively, these findings establish that lactylation-regulated ACSL4 ferroptosis exacerbates MIRI pathogenesis, suggesting that targeting the lactylation-ACSL4 axis represents a promising therapeutic strategy for MIRI.
    Keywords:  ACSL4; Ferroptosis; Hypoxia/reoxygenation; Lactylation; Myocardial ischemia/reperfusion injury
    DOI:  https://doi.org/10.1007/s12265-025-10671-6
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