bims-prolim 2025-10-26 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–10–26
ten papers selected by
Bruna Martins Garcia, CABIMER

Lactate and lactylation: molecular insights into histone and non-histone lactylation in tumor progression, tumor immune microenvironment, and therapeutic strategies.
ZDHHC20-mediated S-palmitoylation of KAP1/TRIM28 promotes DNA damage repair.
ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.
Protein post-translational modifications and tumor immunity: A pan-cancer perspective.
Enrichment of Cysteine S-palmitoylated peptides using Sodium Deoxycholate Acid Precipitation.
Lactate as a Metabolic Regulator in the Tumor Microenvironment: Linking Immunosuppression to Epigenetic Reprogramming.
SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.
Artificial lipidation of proteins and peptides: from mechanism to clinical applications.
LRRC59 inhibits perk pathway‑induced apoptosis and promotes cell proliferation, migration and invasion in colorectal cancer cells.
Succinylation of tumor suppressor PPP2R1A K541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling to display oncogene function.

Biomark Res. 2025 Oct 24. 13(1): 134

Lactate and lactylation: molecular insights into histone and non-histone lactylation in tumor progression, tumor immune microenvironment, and therapeutic strategies.

Shuying Xiao, Suhang Zhang, Kai Sun, Qibo Huang, Qilin Li, Chuanyu Hu.

  Investigating cancer metabolism is of paramount importance for understanding tumor biology and developing novel therapeutic strategies. Lactylation, a posttranslational modification facilitated by the glycolytic product lactate, plays a crucial role in regulating oncogenic signalling pathways. This review provides a comprehensive analysis of lactate metabolism, including its biosynthesis, compartmentalized transport, enzymatic network and structural features of lactate dehydrogenases, transporters, lactyltransferases and deacetylases. These enzymes contribute to malignant tumor progression through metabolic reprogramming and modulation of the immune microenvironment. Importantly, we emphasize that integrating cancer subtype-specific lactylation profiles with core signatures reveals promising therapeutic opportunities for targeting lactate shuttles, histone, and nonhistone lactylation mechanisms, and transcriptional networks regulated by lactylation. In the present review, we highlight the significant potential of targeting glycolysis and lactylation modifications in tumors to improve the efficacy of cancer treatments.

Keywords:  Cancer; Immunotherapy; Lactate; Lactylation

DOI:  https://doi.org/10.1186/s40364-025-00849-0
Oncogene. 2025 Oct 18.

ZDHHC20-mediated S-palmitoylation of KAP1/TRIM28 promotes DNA damage repair.

Zhuang Liu, Han Wang, Yamei Han, Yang Chen, Youyou Wang, Siyue Zhang, Yaqi Mo, Chuanjie Wang, Mingming Xiao, Bo Xu.

S-palmitoylation mediated by the zinc finger aspartate-histidine-histidine-cysteine (ZDHHC) protein acyltransferases (PATs) modulates protein localization, stability, interactions and signal transduction. In this study, we screened the 23 ZDHHC family members and identified ZDHHC20 as one of the major PATs involved in the DNA damage response (DDR). Inhibition of ZDHHC20 expression impaired cellular DNA damage repair capabilities. Meanwhile, data from ZDHHC20 knock-out mice, human tumor cell lines and xenograft tumor models showed that knock-out of ZDHHC20 significantly enhanced radiosensitivity. Using palmitoylation label-free quantitative proteomics, we found that over 600 proteins were palmitoylated in a ZDHHC20-dependent manner. Via the acyl-biotin exchange (ABE) assay, we revealed that KRAB-associated protein 1 (KAP1), also known as tripartite motif-containing protein 28 (Trim28), was palmitoylated at cysteine 232 by ZDHHC20. Notably, ZDHHC20-dependent KAP1 palmitoylation increased the chromatin binding of phosphorylated KAP1, which facilitated chromatin accessibility and subsequent recruitment of the DDR components BRCA1 and 53BP1. Further, we demonstrated that Ataxia-Telangiectasia Mutated (ATM)-dependent phosphorylation of ZDHHC20 at serine 339 increased KAP1 palmitoylation. Taken together, our findings elucidate the role and mechanism of the ATM-ZDHHC20-KAP1 axis in the DDR and provide a novel sensitizing strategy for radiotherapy and chemotherapy.

DOI: https://doi.org/10.1038/s41388-025-03604-9
Adv Sci (Weinh). 2025 Oct 23. e14077

ZDHHC2-Dependent Palmitoylation Dictates Ferroptosis and Castration Sensitivity in Prostate Cancer via Controlling ACSL4 Degradation and Lipid Peroxidation.

Shuai Shao, Wei Li, Yulong Hong, Ruijiang Zeng, Liang Zhu, Lu Yi, Yuan Li, Yinhuai Wang, Haojie Huang, Xuewen Jiang, Xin Jin.

  Ferroptosis represents a promising vulnerability to overcome therapeutic resistance in castration-resistant prostate cancer (CRPC). While S-palmitoylation of lipid peroxide-scavenging proteins such as GPX4 and SLC7A11 has been shown to suppress ferroptosis, whether palmitoylation modulates the lipid peroxidation generation remains unclear. Here, we identified the palmitoyltransferase ZDHHC2 as a critical driver of enzalutamide resistance through destabilizing ACSL4. ZDHHC2 is transcriptionally upregulated by a FOXA1/CXXC5/TET2 complex and promotes S-palmitoylation of the deubiquitinase USP19, which impairs its interaction with ACSL4. This disrupts USP19-mediated ACSL4 stabilization, promoting its ubiquitin-proteasome degradation and consequently suppressing lipid peroxidation and ferroptosis. We developed a small-molecule ZDHHC2 inhibitor, TTZ1, which restores ACSL4 protein, reactivates ferroptosis, and reverses enzalutamide resistance in CRPC cell lines and patient-derived xenograft models. This study uncovers a previously unrecognized mechanism by which palmitoylation regulates ferroptosis through modulating ACSL4 stability, and highlights the ZDHHC2-USP19-ACSL4 axis as a druggable target for overcoming resistance in advanced prostate cancer.

Keywords:  ACSL4; CRPC; ZDHHC2; ferroptosis; lipid peroxide production

DOI:  https://doi.org/10.1002/advs.202514077
Phys Life Rev. 2025 Oct 12. pii: S1571-0645(25)00152-6. [Epub ahead of print]55 142-209

Protein post-translational modifications and tumor immunity: A pan-cancer perspective.

Haoling Zhang, Qilu Yan, Shuya Jiang, Dan Hu, Ping Lu, Shaowei Li, Doblin Sandai, Haolong Zhang, Wangzheqi Zhang, Chenglong Zhu.

  Protein post-translational modifications (PTMs), which involve the covalent attachment of specific chemical groups to amino acid residues, significantly reshape protein structure and function. These modifications play a crucial role in fundamental physiological processes such as signal transduction, metabolic regulation, and protein homeostasis. In the context of pan-cancer, various types of PTMs, including phosphorylation, acetylation, glycosylation, and ubiquitination, create an intricate crosstalk network that finely tunes the stability and function of immune checkpoint molecules, directly influencing tumor immune evasion and immune cell recognition. Additionally, PTMs exert multilayered regulation over the functional states of key immune cells, such as T cells, macrophages, and dendritic cells (DCs), thereby determining the intensity and nature of immune responses within the tumor microenvironment (TME). Furthermore, PTMs are pivotal in antigen processing and presentation by influencing antigen diversity and epitope display, which facilitates tumor cell escape from immune surveillance. Dynamic analyses reveal that PTM landscapes exhibit spatiotemporal specificity during tumor initiation, progression, and metastasis, closely correlating with tumor stage and the establishment of an immunosuppressive microenvironment. Based on these findings, immunotherapeutic strategies targeting key PTM-modifying enzymes, such as kinases, deacetylases, and deubiquitinases, are rapidly emerging. However, these approaches still face challenges, including drug specificity, resistance, and off-target effects. The exploration of synergistic effects through the combinational targeting of distinct PTM pathways, along with a deeper understanding of the interactive regulatory networks among PTMs, opens promising avenues for the development of next-generation precision immunotherapies. This review aims to systematically elucidate the multifaceted roles and dynamic regulation of PTMs in tumor immunity, providing a theoretical foundation and research direction for identifying novel immunotherapeutic targets and optimizing therapeutic strategies.

Keywords:  Antigen presentation; Crosstalk mechanisms; Dynamic regulation; Immune checkpoints; Immune evasion; Pan-cancer perspective; Post-translational modifications (PTMs); Tumor immunity

DOI:  https://doi.org/10.1016/j.plrev.2025.10.001
Mol Cell Proteomics. 2025 Oct 16. pii: S1535-9476(25)00317-2. [Epub ahead of print] 101218

Enrichment of Cysteine S-palmitoylated peptides using Sodium Deoxycholate Acid Precipitation.

Peter T Jensen, Giuseppe Palmisano, Christopher J Rhodes, Martin R Larsen.

S-palmitoylation is a poorly understood post-translational modification that is gaining more attention as an essential regulator of cellular processes. The reversible nature of S-palmitoylation may allow for fine-tuned control of cellular events and adaptation to stimuli. The detection of S-palmitoylated proteins and peptides includes the Acyl-Biotin Exchange (ABE) method, Acyl resin-assisted Capture (Acyl-RAC), metabolic labelling, and derivatives thereof. We present a novel method of enrichment of S-palmitoylated peptides termed SDC Acid Precipitation Enrichment (SDC-ACE). Here, S-palmitoylated peptides are enriched by taking advantage of their co-precipitation with Sodium-Deoxycholate (SDC) under acidic conditions, allowing easy and fast separation of lipidated peptides from the sample suspension. We initially applied our novel method for the characterization of the mouse brain, providing an in-depth analysis of S-palmitoylation events within the brain and comprehensive profile of the mouse brain S-palmitoylome. Further, we applied our method for mapping mouse tissue-specific S-palmitoylation, highlighting the extensive role of S-palmitoylation throughout various organs in the body. Finally, we applied our methods for studying the brain palmitoylome of diabetic db/db mouse, uncovering alterations in the palmitoylation of proteins associated with obesity and type 2 diabetes. The SDC-ACE method allows fast and easy enrichment of S-palmitoylated peptides, providing a valuable tool for exploring the dynamics and function of S-palmitoylation in diverse biological systems.

DOI: https://doi.org/10.1016/j.mcpro.2025.101218
Curr Pharm Biotechnol. 2025 Oct 16.

Lactate as a Metabolic Regulator in the Tumor Microenvironment: Linking Immunosuppression to Epigenetic Reprogramming.

Weiwen Cheng, Pengwei Lai, Xinyuan Liu, Yihan Wang, Xiaohong Du.

  A defining characteristic of tumor cells is their preferential reliance on aerobic glycolysis for lactate production, even under oxygen-sufficient conditions - the well-known Warburg effect. Recent advances have revealed lactate to be far more than a metabolic waste product, establishing its role as a versatile signaling molecule with multiple functions in cancer progression. Acting simultaneously as a pro-inflammatory mediator, hypoxia surrogate, tumor burden indicator, and metastasis predictor, lactate exerts profound and wide-ranging effects on immune cell function within the tumor microenvironment (TME). The immunomodulatory properties of lactate create a profoundly immunosuppressive milieu that facilitates tumor immune evasion. It achieves this through coordinated suppression of antitumor immune effectors, including natural killer cells, dendritic cells, and cytotoxic T lymphocytes, while simultaneously enhancing the immunosuppressive functions of regulatory T cells, tumorassociated macrophages, and endothelial cells. This dual mechanism of action promotes tumor progression and metastasis through multiple pathways. The groundbreaking discovery of lysine lactylation (Kla) has further expanded our understanding of lactate's biological roles, revealing a direct molecular connection between tumor metabolism and epigenetic regulation. This review provides a comprehensive synthesis of current knowledge regarding lactate-mediated immune modulation in the TME, examines recent advances in our understanding of lactate-dependent tumor biology, and evaluates emerging therapeutic strategies that target lactate metabolism. By integrating these perspectives, we aim to offer both fundamental insights and practical guidance for the development of novel anticancer therapies that target metabolic-epigenetic crosstalk.

Keywords:  Cancer therapy.; Immune cells; Immune evasion; Lactate; Tumor microenvironment; lactylation

DOI:  https://doi.org/10.2174/0113892010415740251006000648
Commun Biol. 2025 Oct 20. 8(1): 1485

SIRT5-mediated desuccinylation of MTHFD2 enhances chemoresistance in breast cancer cells by reducing therapy-induced senescence.

Zhang Xianhong, Gao Yue, Zhang Yu, Zhang Yichen, Chen Yufei, Pei Xinke, Zhang Jinhui, Wang Yiqi, Du Yitian, Hao Shuailin, Ni Ting.

Protein lysine succinylation is a crucial post-translational modification that regulates nearly all aspects of eukaryotic and prokaryotic cell, including gene transcription, cell metabolism and redox homeostasis. Among them, metabolic disorders caused by dysfunctional post-translational modifications induce aging and aged-related diseases, including cancer. This study quantified the dynamic changes in protein succinylation in response to DNA damage stress induced by etoposide (ETOP) in tumor cells. A total of 4354 lysine succinylation sites on 1259 proteins were identified, many of which have not been previously reported. Bioinformatics analysis revealed that many proteins are involved in the metabolism of nicotinamide adenine dinucleotide phosphate (NADPH) in mitochondria (including MTHFD2). We further found that low activity or depletion of MTHFD2 enhances the degree of TIS in breast cancer cells and decreases their resistance to chemotherapeutic agents. Interestingly, we also found that SIRT5-mediated desuccinylation of MTHFD2 was able to reduce the senescence of breast cancer cells, thereby enhancing their resistance to chemotherapeutic drugs. This effect may explain the poorer prognosis observed in breast cancer patients with high expression levels of SIRT5 or MTHFD2. These systematic analyses provide new insights into targeting succinylation-modified metabolic proteins to enhance TIS, and their combination with senolytics for breast cancer therapy.

DOI: https://doi.org/10.1038/s42003-025-08878-z
FEBS J. 2025 Oct 23.

Artificial lipidation of proteins and peptides: from mechanism to clinical applications.

Jiaming Mu, Emily Vong, Sheiliza Carmali.

  The landscape of modern medicine has been transformed by protein-based therapeutics, offering targeted treatments for complex disorders with remarkable specificity and efficacy. However, these biologics face significant limitations in clinical settings, including rapid clearance, vulnerability to enzymatic degradation, poor absorption across biological membranes and inefficient distribution within target tissues. Artificial lipidation provides an innovative solution to these challenges, by the deliberate attachment of lipid groups to proteins and peptide structures. This biomimetic approach harnesses principles observed in natural post-translational modifications to create therapeutics with superior pharmacological profiles. By strategically incorporating lipid moieties, researchers can significantly prolong circulation half-life through albumin binding, protect against proteolytic breakdown, facilitate cellular uptake, customize pharmacokinetic parameters and enhance tissue-specific targeting. This Review provides a comprehensive analysis of current lipidation technologies, contrasting covalent modification strategies with noncovalent complexation approaches. We examine the molecular mechanisms underlying the therapeutic benefits, survey successful clinical applications and explore emerging opportunities across diverse therapeutic areas. Through this analysis, we offer insights to guide rational design decisions for developing optimized lipidated biotherapeutics with enhanced clinical performance.

Keywords:  albumin binding; drug delivery; half‐life extension; protein lipidation; therapeutic peptides

DOI:  https://doi.org/10.1111/febs.70298
Oncol Rep. 2026 Jan;pii: 5. [Epub ahead of print]55(1):

LRRC59 inhibits perk pathway‑induced apoptosis and promotes cell proliferation, migration and invasion in colorectal cancer cells.

Xingdong Hou, Yuting Wang, Yuzhuo Chen, Peiyan Zhong, Guangzhi Wang, Baicheng Li, Bowei Lu, Hanyu Jiang, Shili Ning.

  Leucine‑rich repeat‑containing protein 59 (LRRC59), a 244‑amino‑acid endoplasmic reticulum membrane protein, is implicated in the tumorigenesis of multiple malignancies. However, its functional significance in colorectal cancer (CRC) remains poorly understood. In the present study, LRRC59 expression in CRC tissues was evaluated using immunohistochemistry and western blotting. Colony formation, Cell Counting Kit‑8, wound healing and Transwell assays, in in vivo xenograft models, were used to evaluate the effect of LRRC59 on CRC progression. Apoptosis was analyzed using flow cytometry and western blotting. The interaction between LRRC59 and the protein kinase RNA‑like endoplasmic reticulum kinase (PERK) pathway was verified using the starBase database and western blotting. It was found that LRRC59 expression was significantly higher in CRC tissues than in normal tissues. LRRC59 knockdown in HCT116 and LoVo cells inhibited proliferation, migration and invasion and promoted apoptosis, and the PERK pathway was significantly activated. In vivo subcutaneous tumorigenesis assays corroborated these in vitro findings. Treatment with a PERK pathway‑specific inhibitor reduced the apoptosis of HCT116 and LoVo cells with LRRC59 knockdown. These findings suggest that LRRC59 is not only significantly upregulated in CRC but also mechanistically drives tumor progression by coordinating pro‑oncogenic processes, including enhanced proliferation, migration and invasion. Importantly, mechanistic evidence was provided that LRRC59 inhibits apoptosis by suppressing the PERK signaling axis, identifying this molecule a target in the development of CRC therapeutic strategies.

Keywords:  PERK pathway; apoptosis; colorectal cancer; endoplasmic reticulum stress; leucine‑rich repeat‑containing protein 59

DOI:  https://doi.org/10.3892/or.2025.9010
Acta Pharm Sin B. 2025 Oct;15(10): 5294-5311

Succinylation of tumor suppressor PPP2R1A K541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling to display oncogene function.

Guang Yang, Yufei Wang, Hongfeng Yuan, Huihui Zhang, Lina Zhao, Chunyu Hou, Pan Lv, Jihui Hao, Xiaodong Zhang.

  Metabolic reprogramming plays a central role in tumors. However, the key drivers modulating reprogramming of gluconeogenesis/lipogenesis are poorly understood. Here, we try to identify the mechanism by which histone acetyltransferase 1 (HAT1) confers reprogramming of gluconeogenesis/lipogenesis in liver cancer. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced hepatocarcinogenesis was hardly observed in HAT1-knockout mice. Multi-omics identified that HAT1 modulated gluconeogenesis and lipogenesis in liver. Protein phosphatase 2 scaffold subunit alpha (PPP2R1A) promoted gluconeogenesis and inhibited lipogenesis by phosphoenolpyruvate carboxykinase 1 (PCK1) serine 90 dephosphorylation to suppress the tumor growth. HAT1 succinylated PPP2R1A at lysine 541 (K541) to block the assembly of protein phosphatase 2A (PP2A) holoenzyme and interaction with PCK1, resulting in the depression of dephosphorylation of PCK1. HAT1-succinylated PPP2R1A contributed to the remodeling of gluconeogenesis/lipogenesis by PCK1 serine 90 phosphorylation, leading to the inhibition of gluconeogenic enzyme activity and activating sterol regulatory element-binding protein 1 (SREBP1) nuclear accumulation-induced lipogenesis gene expression, which enhanced the tumor growth. In conclusion, succinylation of PPP2R1A lysine 541 by HAT1 converses the role in modulation of gluconeogenesis/lipogenesis remodeling through PCK1 S90 phosphorylation to support liver cancer. Our finding provides new insights into the mechanism by which post-translational modifications (PTMs) confer the conversion of tumor suppressor function to oncogene.

Keywords:  Gluconeogenesis; HAT1; Lipogenesis; Liver cancer; Metabolic remodeling; PCK1 phosphorylation; PPP2R1A; SREBP1; Succinylation

DOI:  https://doi.org/10.1016/j.apsb.2025.07.040