bims-prolim 2025-06-15 papers

Issue of 2025–06–15
seven papers selected by
Bruna Martins Garcia, CABIMER

Biochem Genet. 2025 Jun 07.

LDHA-Mediated H3K18 Lactylation Promotes the Glycolysis in Non-Small Cell Lung Cancer Through Targeting PTEN.

Yufeng Shao, Xiaomin Duan, Guojian Gu, Qingfeng Zhu, Jian Shu, Fan Fei.

Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Lactylation, a lactate-driven post-translational modification, has been implicated in various tumor pathologies. This study aimed to investigate the role of histone H3 lysine 18 lactylation (H3K18la) in NSCLC progression. Western blot was performed to detect the protein levels of lactylation and H3K18la. Cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and Transwell migration assays were performed to detect the cell viability, proliferation, and migration. The 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) uptake rate, lactate content, and extracellular acidification rate (ECAR) were detected by commercial kits. Chromatin immunoprecipitation-qPCR was performed to assess the relative H3K18la enrichment on phosphatase and tensin homolog (PTEN) promoter. Finally, we established the tumor-bearing mouse model. Results showed that A549 and H1299 cells showed increased pan-kla and H3K18la protein levels. Besides, silencing of lactate dehydrogenase A (LDHA) inhibited the cell viability, proliferation, migration, and glycolysis in A549 and H1299 cells. Animal study results indicated that LDHA inhibition suppressed the tumor growth in xenografts mice. Mechanically, LDHA-mediated H3K18la regulated the transcription and stability of PTEN in A549 and H1229 cells. Final rescue results demonstrated that PTEN deficiency increased the cell proliferation, migration, and glycolysis in A549 and H1299 cells. Our study suggested that LDHA-mediated H3K18la promoted the glycolysis in NSCLC through targeting PTEN, which might provide a new insight for NSCLC treatment.

Keywords: Glycolysis; H3K18la; Histone lactylation; Migration; Non-small cell lung cancer; Proliferation

DOI: https://doi.org/10.1007/s10528-025-11145-9

Drug Resist Updat. 2025 Jun 02. pii: S1368-7646(25)00065-2. [Epub ahead of print]82 101264

The shadow of cancer therapeutic resistance: Unveiling the role of S-palmitoylation.

Xue Yang, Mengke Xu, Zhiqin Deng, Bo Xu.

Cancer therapeutic resistance remains a formidable challenge due to its diverse underlying mechanisms. S-palmitoylation (or called S-acylation), a reversible post-translational modification involving the attachment of long-chain fatty acids to cysteine residues, has emerged as a critical regulator of cancer progression and treatment response. This review offers a comprehensive analysis of recent advancements in understanding the role of S-palmitoylation in cancer therapeutic resistance. We examine the intricate relationship between S-palmitoylation and major oncogenic pathways, with particular focus on its distinct contributions to resistance mechanisms in molecularly-targeted therapy, immunotherapy, chemotherapy, radiotherapy, and endocrine therapy. Additionally, we highlight the progress in the proteomic identification and characterization of S-palmitoylated proteins, as well as the development of selective inhibitors targeting protein acyltransferases (PATs) and acyl-protein thioesterases (APTs). Furthermore, we discuss the further directions for developing S-palmitoylation-targeted strategies, providing insights into potential avenues for overcoming cancer treatment resistance.

Keywords: Cancer therapy; Resistance; S-palmitoylation

DOI: https://doi.org/10.1016/j.drup.2025.101264

Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00448-4. [Epub ahead of print]85(11): 2065-2067

No (innate immune) training without lactate.

Jan Van den Bossche.

A recent study in Cell unveils lactate production and downstream histone lactylation as a new player in the induction of trained immunity.1 It provides insight into the intricate metabolic-epigenetic interplay that governs innate immune memory and offers a potential target to reverse maladaptive trained immunity in chronic inflammatory diseases.

DOI: https://doi.org/10.1016/j.molcel.2025.05.014

Transl Oncol. 2025 Jun 05. pii: S1936-5233(25)00158-5. [Epub ahead of print]58 102427

tsRNA-08614 inhibits glycolysis and histone lactylation by ALDH1A3 to confer oxaliplatin sensitivity in colorectal cancer.

Zhengbo Chen, Yiyang Zhang, Fang Yan, Gang Zhao, Yan Wang.

BACKGROUND: Enhanced glycolysis contributes to the chemotherapy resistance of colorectal cancer (CRC). However, whether tRNA-derived small RNAs (tsRNAs) regulate CRC oxaliplatin sensitivity through glycolysis-mediated histone lactylation remains unclear.
METHODS: By analyzing RNA-seq data from CRC samples in the TCGA database, we identified a glucose metabolism-related tsRNA. Overexpression of tsRNA-08614 was investigated to explore its impact on CRC sensitivity to oxaliplatin. The targeting gene of tsRNA-08614 was validated through a dual-luciferase reporter assay. The specific molecular mechanism of tsRNA-08614 regulating CRC oxaliplatin sensitivity was further revealed by ChIP-seq and RNA-seq.
RESULTS: We found a down-regulated tsRNA-08614 targeted glycolysis-related gene, which was associated with chemotherapy resistance. Overexpression of tsRNA-08614 promoted oxaliplatin sensitivity of CRC cells. tsRNA-08614 inhibited the expression of the target gene ALDH1A3 and reduced glycolysis, whereas the glycolytic inducer reversed the enhanced sensitivity caused by tsRNA-08614. Interference of tsRNA-08614 increased H3K18la and pan-Kla levels, while the lactate inhibitor partially suppressed these effects. Furthermore, overexpression of tsRNA-08614 reprogrammed the transcription of genes mediated by histone lactylation modification, with EFHD2 showing the most significant differential expression. EFHD2 inhibited the sensitivity of CRC cells to oxaliplatin by upregulating CMPK2 and enhancing mitochondrial function. Finally, we demonstrated that tsRNA-08614 enhanced sensitivity to oxaliplatin in CRC by reducing histone lactylation levels in vivo.
CONCLUSION: tsRNA-08614 regulates ALDH1A3 to inhibit glycolysis and histone lactylation modification, thereby suppressing the transcriptional activity of EFHD2 and ultimately promoting the sensitivity of CRC to oxaliplatin. These findings suggest that tsRNA-08614 may represent a novel molecular target to combat oxaliplatin resistance in CRC chemotherapy.

Keywords: Colorectal cancer; Glycolysis; Histone lactylation; tsRNA

DOI: https://doi.org/10.1016/j.tranon.2025.102427

Cell Rep. 2025 Jun 09. pii: S2211-1247(25)00545-5. [Epub ahead of print]44(6): 115774

GCLM lactylation mediated by ACAT2 promotes ferroptosis resistance in KRASG12D-mutant cancer.

Yubin Chen, Qian Yan, Shiye Ruan, Jinwei Cui, Zhenchong Li, Zhongyan Zhang, Jiayu Yang, Jike Fang, SiYang Liu, Shanzhou Huang, Baohua Hou, Chuanzhao Zhang.

KRAS mutations drive tumorigenesis, but their role in ferroptosis regulation remains unclear. Here, we construct wild-type KRAS (KRASWT) and KRASG12D-mutant cancer cells and demonstrate that G12D-mutant cells exhibit increased viability and reduced ferroptosis upon RSL3 or erastin treatment. These cells show diminished lipid peroxidation and mitochondrial damage, indicating ferroptosis resistance. KRASG12D activates MEK/ERK signaling to phosphorylate LDHA, enhancing glycolysis and lactate production. Exogenous lactate supplementation similarly protects WT cells from ferroptosis. Mechanistically, G12D-mutation-derived lactate induces glutamate-cysteine ligase (GCL) modifier (GCLM) lactylation, a process catalyzed by acetyl-coenzyme A (CoA) acetyltransferase 2 (ACAT2). Inhibition of GCLM lactylation either through the mutation of the lactylation site or by knockdown of ACAT2 diminished the enzymatic activity of GCL and suppressed glutathione synthesis. Importantly, ACAT2 depletion overcomes ferroptosis resistance in KRASG12D-mutant tumors in vivo. Our findings reveal a KRASG12D-driven metabolic adaptation linking GCLM lactylation to ferroptosis resistance, proposing ACAT2 inhibition as a therapeutic strategy for KRAS-mutant cancers.

Keywords: CP: Cancer; CP: Metabolism; GCLM; KRAS mutation; ferroptosis; glutamate-cysteine ligase modifier; pancreatic cancer; protein lactylation

DOI: https://doi.org/10.1016/j.celrep.2025.115774

Nat Immunol. 2025 Jun 10.

Targeting lactylation reinforces NK cell cytotoxicity within the tumor microenvironment.

Jing Jin, Peidong Yan, Dongyao Wang, Lin Bai, Hao Liang, Xiaoyu Zhu, Huaiping Zhu, Chen Ding, Haiming Wei, Yi Wang.

Dysfunction of natural killer (NK) cells can be associated with tumor-derived lactate in the tumor microenvironment. Lactate-induced lysine lactylation (Kla) is a posttranslational modification, and strategies aimed at augmenting NK cell resistance to Kla might enhance cytotoxicity. Here we show that increased Kla levels in NK cells are accompanied by impaired nicotinamide adenine dinucleotide metabolism, fragmented mitochondria and reduced cytotoxicity. Supplementation with nicotinamide riboside (a nicotinamide adenine dinucleotide precursor) and honokiol (a SIRT3 activator) enhanced NK cell cytotoxicity by reducing cellular Kla levels. This combination restores antileukemic activity of NK cells in vivo and ex vivo by modulating Kla on ROCK1, thereby inhibiting ROCK1-DRP1 signaling to prevent mitochondrial fragmentation. Altogether, this study shows how lactylation can compromise NK cells and highlights this lactylation as a target for NK cell-based immunotherapy to enhance resilience to lactate in the tumor microenvironment.

DOI: https://doi.org/10.1038/s41590-025-02178-8

Acta Pharmacol Sin. 2025 Jun 11.

Targeting PPARα activation sensitizes glioblastoma cells to temozolomide and reverses acquired resistance by inhibiting H3K18 lactylation.

Zhen-Chuan Wang, Chen Li, Zhao Zhang, Shan Lu, Ying-Min Liu, Peng Qi, Xi Chen, Yu-Bo Wang, Wen-Jie Feng, Cheng-Liang Pan, Qing-Xuan Wang, Zhi-Lin Ji, Ying Yu, Mei-Hua Piao, Guang-Fan Chi, Peng-Fei Ge.

Temozolomide (TMZ) is an alkylating agent recommended as the first-line pharmaceutical for glioblastoma (GBM), but its efficacy is limited by the development of acquired resistance in GBM cells. TMZ resistance is regulated by multiple factors such as MGMT upregulation and metabolism reprogramming, its underlying mechanism still remains elusive. Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor regulating the metabolism of lipid and glucose, while histone 3 lactylation at lysine on position 18 (H3K18la) could promote cancer cells' resistance to therapeutic drugs. In this study we investigated the role of PPARα in regulating H3K18la and TMZ sensitivity in glioblastoma (GBM) cells. We established TMZ-resistant U87TR, U251TR, and U118TR cells by treating the parental U87, U251, and U118 cells with increased dosages of TMZ until the cells could resist TMZ (200 μM). We found that in TMZ-resistant cells, H3K18la level was apparently upregulated accompanied by increased ECAR (extracellular acidification rate) and intracellular lactate levels, whereas lactate (20 mM) time-dependently upregulated H3K18la in U87 and U251 cells. We found that PPARα was activated by TMZ in U87, U251, and U118 cells, but was inactivated when the cells became resistant to TMZ. In TMZ-sensitive glioma cells, TMZ triggered PPARα activation by causing DNA DSBs-dependent p38 MAPK activation. The activated PPARα upregulated its downstream signal ACOX1, which not only inhibited lactate-mediated H3K18 lactylation by promoting ROS-dependent PKM2 downregulation, but also reversely enhanced PPARα activation through ROS-activated ASK1/p38 MAPK pathway. In GBM cells resistant to TMZ, PPARα and p38 MAPK were both inactivated, but H3K18 lactylation was obviously upregulated. Targeting activation of PPARα with gemfibrozil or GW7647 not only sensitized GBM cells to TMZ but also effectively reversed the acquired resistance of GBM cells to TMZ by suppression of H3K18 lactylation through upregulation of ACOX1. Taken together, PPARα contributed to TMZ-induced growth arrest in GBM cells by inhibiting lactate-mediated H3K18 lactylation, targeting activation of PPARα may be a new strategy to improve the treatment effect of TMZ against GBM.

Keywords: ACOX1; H3K18 lactylation; PKM2; PPARα; glioblastoma; temozolomide resistance

DOI: https://doi.org/10.1038/s41401-025-01600-z