bims-prolim 2025-08-03 papers

Issue of 2025–08–03
seven papers selected by
Bruna Martins Garcia, CABIMER

Biochim Biophys Acta Rev Cancer. 2025 Jul 30. pii: S0304-419X(25)00141-6. [Epub ahead of print] 189399

Lactylation: A new direction for tumor-targeted therapy.

Dan Deng, Yan Luo, Yun Hong, Xing Ren, Xuyu Zu, Jianbo Feng.

Lactate, a central metabolite generated during glycolysis, functions not only as a by-product but also as a critical signalling mediator, profoundly influencing tumor progression and cellular destiny. Among the post-translational modifications, lactylation-a novel modification driven by lactate-has emerged as a transformative discovery, reshaping our understanding of lactate's role within the tumor microenvironment (TME). This modification bridges metabolic reprogramming and epigenetic regulation, unveiling previously unexplored dimensions of tumor biology. Recent findings demonstrate that protein lactylation in tumor cells, cancer stem cells, and immune cells infiltrating the TME can modulate transcriptional activities, thereby influencing tumor initiation, progression, and immune evasion. These insights position lactylation as a promising target for new therapeutic strategies in cancer. This review expounds on the underlying mechanisms of lactylation, including the identification of the "writers" and "erasers" involved in protein lactylation, and highlights the physiological significance of lactylation across diverse biological contexts. Furthermore, the paper emphasized on the latest advancements in understanding the modulatory functions of protein lactylation within pathological processes, the potential for targeting lactylation sites, and underscores the scientific significance for future investigative endeavours.

Keywords: Immunotherapy; Lactate; Lactylation; Post-translational modifications; Tumor microenvironment; Tumor-targeted therapy

DOI: https://doi.org/10.1016/j.bbcan.2025.189399

Cancer Lett. 2025 Jul 26. pii: S0304-3835(25)00526-9. [Epub ahead of print]631 217957

O-GlcNAcylation of YBX1 drives a glycolysis-histone lactylation feedback loop in hepatocellular carcinoma.

Yang Ji, Zhenggang Xu, Lei Tang, Tianyu Huang, Xiaoxin Mu, Chuangye Ni, Bai Tang, Hao Lu, Chuanyong Zhang, Shikun Yang, Xuehao Wang.

Metabolic reprogramming is a hallmark of tumorigenesis and progression, with alterations in glucose metabolism, often referred to as the Warburg effect, playing a central role. This shift allows tumor cells to rapidly acquire energy and generate essential metabolic intermediates, thereby supporting enhanced growth. Despite its significance, the mechanisms by which tumor cells upregulate glycolysis remain inadequately understood. In this study, we report that YBX1 is highly expressed in hepatocellular carcinoma (HCC) and is closely associated with glycolysis. We show that YBX1 is modified by O-linked N-acetylglucosamine (O-GlcNAc) at threonine 57 (T57), which stabilizes the protein and increases its expression. This modification also promotes the phosphorylation of YBX1 at serine 102, facilitating its nuclear translocation. Consequently, this process enhances the transcription of glycolysis-related genes and stimulates lactate production. Moreover, YBX1 activates the transcription of P300, which in turn drives the lactylation of histones, particularly H3K18la. Cleavage Under Targets and Tagmentation (CUT&Tag) analysis reveals that H3K18 lactylation positively regulates YBX1 gene transcription. Our findings establish a positive feedback loop involving YBX1, glycolysis, and H3K18 lactylation that accelerates HCC progression. Disrupting this feedback loop may provide a novel therapeutic strategy for HCC.

Keywords: Histone lactylation; OGT; Post-translational modification; Warburg effect; YBX1

DOI: https://doi.org/10.1016/j.canlet.2025.217957

Int J Mol Med. 2025 Oct;pii: 163. [Epub ahead of print]56(4):

How lactate and lactylation shape the immunity system in atherosclerosis (Review).

Yan Xiong, Jie Zhou, Junru Wang, Hui Huang.

Atherosclerosis is a leading cause of cardiovascular diseases, causing significant morbidity and mortality. This review article examines the role of lactate and lactylation in atherosclerosis, a chronic inflammatory disease closely linked to lipid metabolism and immune system activation. Lactate, a metabolic byproduct and signaling molecule, has emerged as a key regulator of immune cell functions and epigenetic modifications. The article explores the mechanisms through which lactate and lactylation influence macrophage polarization, T‑cell differentiation and B‑cell metabolism, highlighting their complex dual roles in the progression of atherosclerosis. By modulating metabolic reprogramming, functional polarization and epigenetic regulation, lactate and lactylation significantly impact plaque formation and stability. These findings provide a foundation for developing novel therapeutic strategies targeting lactate metabolism and lactylation pathways.

Keywords: atherosclerosis; epigenetic modifications; immune system; lactate; lactylation; metabolic reprogramming

DOI: https://doi.org/10.3892/ijmm.2025.5604

Biomolecules. 2025 Jul 14. pii: 1010. [Epub ahead of print]15(7):

Context Matters: Divergent Roles of Exercise-Induced and Tumor-Derived Lactate in Cancer.

Amir Hossein Ahmadi Hekmatikar, Ghazal Zolfaghari, Aref Basereh, D Maryama Awang Daud, Kayvan Khoramipour.

Instead of being waste product of metabolism, lactate, has become a key metabolic and signaling molecule in both exercise physiology and tumor biology. Carcinogenic cells produce huge amounts of lactate through the Warburg effect, which is a hallmark of aggressive tumors, increasing acidity in the environment that can stimulates angiogenesis, immune evasion, and metastasis. Conversely, while exercise acutely elevates blood lactate concentration but it consider helpful for cancer patients. This paradox raises the following question: is exercise-induced lactate a friend or foe in cancer? This study reviews current evidence on the mechanistic, metabolic, immunological, and clinical impacts of exercise-induced lactate in cancer patients, highlighting the context-dependent effects that render lactate either beneficial or detrimental. Tumor-derived lactate seems to be pro-tumorigenic, driving immune suppression and disease progression, whereas short bursts of lactate from exercise can enhance anti-tumor immunity and metabolic reprogramming under the right conditions. Therefore, lactate's impact on cancer is "all about the context".

Keywords: cancer; exercise; lactate; metabolism

DOI: https://doi.org/10.3390/biom15071010

Pharmaceutics. 2025 Jun 25. pii: 825. [Epub ahead of print]17(7):

Palmitoylation Transduces the Regulation of Epidermal Growth Factor to Organic Anion Transporter 3.

Zhou Yu, Jinghui Zhang, Jiaxu Feng, Guofeng You.

Background: Organic anion transporter 3 (OAT3) in the kidney proximal tubule cells plays a critical role in renal clearance of numerous endogenous metabolites and exogenous drugs and toxins. In this study, we discovered that epidermal growth factor (EGF) regulates the expression and activity of OAT3 through palmitoylation, a novel mechanism that has never been described in the OAT field. Methods/Results: Our results showed that treatment of OAT3-expressing cells with EGF led to a ~40% increase in OAT3 expression and OAT3-mediated transport of estrone sulfate, a prototypical substrate for OAT3. EGF-stimulated OAT3 transport activity was abrogated by H-89, a protein kinase A (PKA) inhibitor, indicating that an EGF-PKA signaling pathway is involved in the regulation of OAT3. We also showed that treatment of OAT3-expressing cells with EGF resulted in an enhancement of OAT3 palmitoylation, a novel type of post-translational modification for OATs, and such an enhancement was blocked by H-89, suggesting that the EGF-PKA signaling pathway participated in the modulation of OAT3 palmitoylation. Palmitoylation was catalyzed by a group of palmitoyltransfereases, and we showed that OAT3 palmitoylation and expression were inhibited by 2-BP, a general inhibitor for palmitoyltransfereases. We also explored the relationship among EGF/PKA signaling, OAT palmitoylation, and OAT transport activity. We treated OAT3-expressing cells with EGF or Bt2-cAMP, a PKA activator, in the presence and absence of 2-BP, followed by the measurement of OAT3-mediated transport of estrone sulfate. We showed that both EGF- and Bt2-cAMP-stimulated OAT3 transport activity were abolished by 2-BP, suggesting that palmitoylation mediates the regulation of EGF/PKA on OAT3. Finally, we showed that osimertinib, an anti-cancer drug/EGFR inhibitor, blocked EGF-stimulated OAT3 transport activity. Conclusions: In summary, we provided the first evidence that palmitoylation transduces the EGF/PKA signaling pathway to the modulation of OAT3 expression and function. Our study also provided an important implication that during comorbidity therapies, EGFR inhibitor drugs could potentially decrease the transport activity of renal OAT3, which would subsequently alter the therapeutic efficacy and toxicity of many co-medications that are OAT3 substrates.

Keywords: epidermal growth factor; organic anion transporter 3; palmitoylation; protein kinase A; regulation; signaling pathway; transporter

DOI: https://doi.org/10.3390/pharmaceutics17070825

Front Immunol. 2025 ;16 1585727

Lactylation prognostic signature identifies DHCR7 as a modulator of chemoresistance and immunotherapy efficacy in bladder cancer.

Yuanqiao Zhao, Zhuo Xing, Yongqi Zhao, Haozhe Xu, Ruilin Liu, Tiejun Yang, Yinhuai Wang, Xuan Zhu.

Background: Bladder cancer (BLCA), the 10th most common cancer worldwide, presents a worsening prognosis as the disease progresses. Reliable tools for predicting BLCA prognosis and treatment efficacy remain urgently needed.
Methods: Expression profiles of lactylation related genes were analyzed utilizing the Cancer Genome Atlas (TCGA) database and BLCA data from the GSE13507 dataset. Two distinct clusters were identified through unsupervised clustering analysis. Lactylation associated gene signatures were established and subsequently validated using training cohort and different validation cohorts. Immune cell infiltration patterns and drug response profiles were systematically evaluated. Parallel analyses of lactylation related genes were conducted at the single-cell resolution. A series of in vivo and in vitro experiments were subsequently performed to validate the findings.
Results: We examined the mRNA expression profiles of 22 lactylation related genes in BLCA tissues. Through comprehensive analysis, we identified two distinct lactylation clusters that exhibited significantly different clinical outcomes and tumor immune microenvironment characteristics. Building upon these findings, we subsequently stratified patients into two molecular subtypes according to the lactylation clusters and established a robust genetic signature for predicting survival outcomes in BLCA patients. The lactylation risk score showed a strong connection with survival outcomes and correlated with the tumor microenvironment (TME) immunosignature and predicted immunotherapy efficacy. DHCR7 emerged as a pivotal prognostic gene from the nine gene model, prompting subsequent focused analyses. Single-cell analysis confirmed that DHCR7 reached peak expression in tumor epithelial cells, whereas TCGA data and single-cell data demonstrated strong associations between DHCR7 and diverse immune-cell populations. For the first time, we identified that knockdown of DHCR7 enhances the efficacy of both cisplatin chemotherapy and immunotherapy, highlighting DHCR7 as a key player in cisplatin resistance and its influence on immunotherapy effectiveness in BLCA. These findings offer valuable insights into potential combined therapeutic strategies.
Conclusions: We developed a robust lactylation risk prediction model for accurately forecasting BLCA prognosis and identified DHCR7 as a pivotal biomarker involved in cisplatin resistance and influencing immunotherapy efficacy in BLCA.

Keywords: Dhcr7; bladder cancer; chemotherapy; immunotherapy; lactylation; prognostic signature; tumor immune microenvironment

DOI: https://doi.org/10.3389/fimmu.2025.1585727