Lactylation in urological malignancies: emerging mechanisms and therapeutic direction.

In RCC, the role of lactylation—particularly histone lactylation—is also significant ( Table 1 ; Figure 5 ). VHL inactivation is a key driver event in clear cell RCC (ccRCC) ( Cotta et al., 2023 ), which promotes enhanced glycolysis and lactate accumulation through a HIF-dependent mechanism, thereby inducing H3K18la. H3K18la recruits EP300 to activate the transcription of platelet-derived growth factor receptor β (PDGFRβ), and PDGFRβ signaling in turn further promotes glycolysis and lactate production, forming a positive feedback loop that drives tumor proliferation and metastasis ( Yang et al., 2022 ). Similarly, in a mouse model of RCC brain metastasis, the metabolite L-2-hydroxyglutarate upregulates the transcription of HIF1α by promoting H3K18la, thereby suppressing ferroptosis in tumor cells, enhancing their proliferative and migratory capacities, and facilitating RCC brain metastasis ( Liu et al., 2025g ). Additionally, FKBP10 binds to LDHA and promotes its phosphorylation, enhancing LDHA activity and lactate production. This subsequently induces histone lactylation modifications such as H3K14la and H3K18la, regulating the expression of metabolism-related genes to facilitate ccRCC progression ( Liu et al., 2024 ). Histone lactylation is also closely linked to immune evasion in RCC. Studies have shown that NSUN2 stabilizes NEO1 mRNA through an m 5 C-dependent mechanism, enhancing glycolysis and elevating H3K18la levels. The latter upregulates PD-L1 via the MYC/POM121/CD274 axis, mediating immune escape ( Wang K. et al., 2025 ). Furthermore, in the TME, lactate accumulation resulting from VHL mutation regulates the activation of cancer-associated fibroblasts (CAF) through histone lactylation, exacerbating immunosuppression ( Kong et al., 2024 ). The role and mechanism of lactylation in renal cell carcinoma. Non-histone lactylation also plays an important role in the malignant progression of RCC. On one hand, hypoxia induces p300-mediated lactylation of YTHDC1, enhancing its phase separation ability and promoting the formation of nuclear condensates. These condensates protect the mRNAs of oncogenes such as BCL2 and E2F2 from degradation by the PAXT complex, thereby facilitating RCC progression ( Dai et al., 2025 ). On the other hand, in RCC, KAT8-catalyzed lactylation of mitochondrial malate dehydrogenase 2 (MDH2) enhances its enzymatic activity, which it elevating NADPH levels through an IDH1-dependent pathway mediated by the MDH2/CS/SLC25A1 complex, this helps tumor cells resist oxidative stress and maintain mitochondrial function, ultimately promoting the proliferation, migration, and invasion of RCC cells ( Tang et al., 2025b ). Although research on non-histone lactylation in renal cancer remains limited, its potential should not be overlooked. Similarly, prognostic models constructed based on LRGs show great potential for clinical application in RCC patients. A study focusing on LRGs in CAFs identified TIMP1 as a hub gene, whose high expression is significantly associated with poor prognosis in ccRCC patients and may serve as a predictor of tumor aggressiveness ( Kong et al., 2024 ). Furthermore, a risk model integrating LRGs and m 6 A-related genes effectively distinguished survival outcomes among ccRCC patients. The high-risk group exhibited higher tumor mutation burden and microsatellite instability, along with increased sensitivity to immunotherapy ( Yang L. et al., 2023 ). These models offer promising directions for prognostic prediction in RCC, though further research is needed to validate their predictive value.

Urological malignancies, which include bladder cancer (BC), prostate cancer (PCa), and renal cell carcinoma (RCC), are among the most prevalent malignancies worldwide. These cancers pose significant clinical challenges due to their high incidence, frequent recurrence, and therapeutic resistance ( Maughan et al., 2025 ; Barata et al., 2025 ). Among them, BC stands out as one of the most common urological malignancies, characterized by a high recurrence rate, chemoresistance, and an immunosuppressive tumor microenvironment (TME), all of which contribute to poor patient prognosis ( Galsky et al., 2025 ; Scilipoti et al., 2025 ; Dyrskjøt et al., 2023 ). PCa, a leading malignancy in men, frequently develops resistance to hormonal therapies such as enzalutamide and may undergo neuroendocrine differentiation, leading to treatment failure ( Nouruzi et al., 2025 ; Francini et al., 2025 ). RCC is notably driven by metabolic reprogramming; inactivation of the VHL gene dysregulates hypoxia signaling pathways and enhances the Warburg effect, rendering it largely refractory to conventional radiotherapy and chemotherapy and limiting available treatment options ( Larcher et al., 2025 ; Choueiri et al., 2020 ; Chappell et al., 2019 ). Both metabolic reprogramming and epigenetic alterations have been firmly established as central mechanisms in the pathogenesis of urological malignancies ( Knowles and Hurst, 2015 ; Markowski et al., 2019 ; Davies et al., 2023 ). In recent years, the convergence of metabolic biology and epigenetics has unveiled lactylation—a novel form of post-translational modification (PTM)—as a key mechanism underlying malignant progression. This emerging field offers novel insights into the pathogenesis of urological malignancies and opens promising avenues for the development of innovative therapeutic strategies ( Zhang et al., 2019 ; Hou et al., 2025 ). Lactylation is a PTM in which lactate, a key metabolic intermediate, covalently binds to lysine residues on proteins. This process is dynamically regulated by intracellular lactate levels, lactyltransferases, and delactylases ( Sheng X. et al., 2025 ; Zhang Q. et al., 2025 ). Initially identified on histones (e.g., H3K18la, H4K12la), lactylation modulates gene transcription by altering chromatin accessibility ( Zhang et al., 2019 ). Subsequent studies have revealed that lactylation also occurs on diverse non-histone proteins—including metabolic enzymes, signaling molecules, and DNA repair factors—where it regulates protein stability, enzymatic activity, and subcellular localization, thereby influencing critical cellular processes such as metabolism, signal transduction, and DNA damage response ( Peng and Du, 2025 ; Li Z. et al., 2025 ). Moving beyond the conventional view of lactate as merely a metabolic waste product, lactylation represents a fundamental mechanism that bridges cellular metabolism and epigenetic regulation. It serves as a crucial molecular link through which tumor microenvironmental—such as hypoxia and enhanced glycolysis—shape cellular phenotypes in cancer ( Rho and Hay, 2025 ; Llibre et al., 2025 ). Recent studies have confirmed the regulatory role of lactylation in urological malignancies, demonstrating tumor-type specificity and complex mechanisms. Although the mechanisms vary, lactylation plays an important role in tumor proliferation, metastasis, and drug resistance. Targeting lactylation may represent a potential therapeutic strategy for urological malignancies. Additionally, prognostic models based on lactation-related genes (LRGs) have shown good predictive value in urological malignancies, effectively predicting patient survival and treatment responses. Although significant progress has been made in lactylation-related research in urological tumors, there remains no targeted systematic review in this field. Thus, there is an urgent need to synthesize existing findings in order to provide direction for future developments. This review first summarizes the classification and regulatory mechanisms of lactylation, then outlines its common roles in cancer. Furthermore, it focuses on lactylation’s functions and mechanisms in various urological malignancies. Finally, we summarize current research challenges and outline future directions, providing theoretical foundations for elucidating metabolic-epigenetic regulatory patterns in urological malignancies and advancing clinical translation research.

Lactylation, a novel PTM that has garnered significant attention across various fields in recent years, dynamically regulates gene transcription and protein functions. As an essential initiator of lactylation, lactate is primarily obtained through two pathways within cells: the first involves glucose entering via glucose transporters and producing lactate through glycolysis; the second allows lactate to directly enter cells through receptors like monocarboxylic acid transporters ( Chen et al., 2025a ; Chen J. et al., 2025 ; Fan et al., 2025 ). Upon reaching the cytoplasm, lactate does not bind directly to lysine but must first be converted into L-lactoyl-CoA via L-lactoyl-CoA synthetase—a crucial prerequisite for subsequent binding reactions ( Peng and Du, 2025 ). Due to the presence of two somers (L-and D-lactate), lactylation forms two distinct pathways: L-lactoylation and D-lactoylation ( Sheng X. et al., 2025 ; Iozzo et al., 2025 ) with the former primarily involving enzymatic lactylation and the latter non-enzymatic lactylation. After binding to lysine, lactate further generates three structural isomers: K L-la , K D-la , and K ce ( Peng and Du, 2025 ; Zhang D. et al., 2025 ). This review outlines the classification and regulatory mechanisms of lactylation ( Figure 1 ). Classification and mechanism of lactylation. Mechanistically, lactylation can be divided into enzyme-catalyzed lactylation and non-enzyme-catalyzed lactylation. In terms of the modified target, lactylation can be divided into histone lactylation and non-histone lactylation. Based on differences in catalytic mechanisms, lactylation can be further categorized into enzymatic and non-enzymatic lactylation ( Deng D. et al., 2025 ). Enzymatic lactylation relies on specific transferases for catalysis, with classical acetyltransferases such as p300 and TIP60 serving as primary mediators ( Liu Z. et al., 2025 ; Yang et al., 2025 ; Li C. et al., 2025 ). Studies have confirmed that p300 acts as a core “writer” for lactylation of various histones and non-histone proteins, transferring the lactyl group to target proteins and thereby regulating gene transcription and protein expression ( Liu J. et al., 2025 ; Tang et al., 2025a ). In addition, HBO1, GCN5, and MOF have also been identified as writers of lactylation, catalyzing lactylation on a range of histone and non-histone proteins ( Zou et al., 2025 ; Niu et al., 2024 ; Sun C. et al., 2025 ). Interestingly, alanyl-tRNA synthetase 1 (AARS1) and AARS2 can directly utilize lactate and ATP to catalyze protein lactylation independently of lactyl-CoA ( Li H. et al., 2024 ). Specifically, AARS1 promotes tumorigenesis by regulating lactylation of p53 ( Zong et al., 2024 ), while AARS2 mediates lactylation of carnitine palmitoyltransferase 2 (CPT2), thereby inhibiting its enzymatic activity and influencing energy metabolism ( Mao et al., 2024 ). In contrast to enzymatic lactylation, evidence for non-enzymatic lactylation remains limited. This process occurs spontaneously under conditions of high lactate concentration or in acidic microenvironments. For instance, in scenarios of glycolytic disruption, D-lactate can undergo non-enzymatic conjugation with lysine residues via lactylglutathione to form K D-La ( Gaffney et al., 2020 ). Lactylation can be classified into two major categories based on the modified substrate: histone lactylation and non-histone lactylation. Histone lactylation, the first type of lactylation to be discovered, was initially identified in human histones by Zhao et al., in 2019, who detected 28 lactylation sites primarily located on lysine residues of histone H3 and H4 ( Zhang et al., 2019 ). Subsequent studies revealed that additional sites such as H3K9 and H3K14, can also undergo lactylation. Many of these newly identified sites are distributed in promoter or enhancer regions of genes, where they regulate gene transcription and play broad roles in various physiological and pathological processes in humans, particularly in the progression of tumor diseases ( Zong et al., 2025 ; Yan et al., 2025 ). For example, H4K12la enhances glycolysis in endometrial cells by regulating HIF1-α, thereby improving pregnancy outcomes ( Zhao et al., 2023 ). H3K18la inhibits ferroptosis through the NF-κB pathway, leading to resistance to enzalutamide in PCa ( Ji et al., 2025 ). H3K9la activates SLC7A11 and promotes microglial activation in a mouse model of Parkinson’s disease ( Qin et al., 2025 ). Recent studies have shown that lactylation can also occur on non-histone proteins. Lactylation widely modifies lysine residues on non-histone proteins, thereby influencing protein stability and function, ultimately regulating the progression of various diseases, especially cancers ( Chen et al., 2024 ). For instance, lactylation of p53 contributes to enzalutamide resistance in PCa. Lactylation of RAD51 enhances homologous recombination repair, thereby conferring cisplatin resistance in ovarian cancer ( Sun C. et al., 2025 ). Notably, metabolic enzymes such as pyruvate kinase M2 (PKM2) and enolase can also undergo lactylation, which directly participates in glycolytic reprogramming by altering substrate binding capacity or enzymatic activity ( Zong et al., 2025 ; Wang J. et al., 2022 ; Shao et al., 2025 ). Lactylation is a dynamic and reversible process. Similar to other PTMs, its regulation relies on the precise collaboration of Writers, Erasers, and Readers ( Wang Y. et al., 2025 ). Writers primarily catalyze lactylation through the catalytic transfer of lactyl groups, with the acetyltransferase family being extensively studied as key contributors. Particularly, p300 plays a central role in regulating lactylation across various histones and non-histone proteins ( Liu R. et al., 2025 ; Fang et al., 2025 ; Zeng et al., 2023 ). Additionally, GCN5 promotes myocardial repair gene activation by catalyzing H3K18la ( Wang N. et al., 2022 ). KAT8, which modifies multiple substrates, enhances collagen production to combat skin aging by regulating H4K12la ( Zou et al., 2025 ). AARS1 accelerates endometriosis progression by promoting Snail1 lactylation ( Liu L. et al., 2025 ), while AARS2 inhibits mitochondrial metabolism by modifying CPT2 via racemization ( Mao et al., 2024 ). Furthermore, studies have identified YiaC, HBO1, GCN5, GNAT13, HDAC6, and others as Contributors to racemization ( Peng and Du, 2025 ; Niu et al., 2024 ; Dong et al., 2022 ; Sun W. et al., 2023 ; Li et al., 2023 ; Sun et al., 2024 ). Erasers function by removing lactyl groups, with HDACs serving as the primary family of delactylases. For example, HDAC1 can reverse ASH2L lactylation, thereby inhibiting angiogenesis and malignant progression in hepatocellular carcinoma (HCC) ( Han et al., 2025 ). Similarly, HDAC2 also suppresses angiogenesis by reducing H3K9la ( Fan et al., 2024 ). The sirtuin family exerts delactylation activity in an NAD + -dependent manner. For instance, SIRT1 reverses HADHA lactylation and ameliorates sepsis-induced cardiac dysfunction ( Zhang TN. et al., 2025 ). SIRT2 inhibits cuproptosis in gastric cancer by suppressing methyltransferase 16 (METTL16) lactylation ( Sun L. et al., 2023 ). Additionally, CobB has been identified as a novel lysine lactylation eraser that modulates PykF activity by removing its lactylation modification ( Dong et al., 2022 ). Furthermore, HDAC3 and SIRT3 have also been recognized as erasers of lactylation ( Sun M. et al., 2025 ; Chen et al., 2025c ). Readers function by recognizing lactylation. Currently, the only identified Readers are DPF2, Brg1, and TRIM33. Among these, TRIM33 represents a novel histone lactylation reader that regulates the expression of inflammatory genes in activated macrophages and mediates the polarization process of M2-type macrophages ( Nuñez et al., 2024 ). DPF2 promotes tumorigenesis by reading lactylation of H3K14 and driving the transcription of cancer-related genes ( Zhai et al., 2024 ). Brg1 facilitates mesenchymal–epithelial transition in pluripotent stem cells by recognizing lactylation signals at H3K18 ( Hu et al., 2024 ). The identification of these readers provides critical insights into how lactylation precisely regulates gene expression.

As a novel PTM linking cellular metabolism and epigenetics, lactylation has demonstrated substantial potential for clinical application in urological tumors. Current studies have established that histone lactylation regulates the transcription of key genes such as ZEB1 and PDGFRβ by remodeling chromatin structure, participating in processes like EMT in BC and proliferation and metastasis in RCC. Non-histone lactylation influences core biological processes such as DNA repair and mRNA stability by modulating protein stability, enzymatic activity, or subcellular localization, thereby mediating drug resistance and malignant progression in tumors. Meanwhile, prognostic models constructed based on LRGs demonstrate clinical value in stratifying patient risk, predicting treatment response, and estimating survival outcomes, offering potential tools for personalized diagnosis and treatment. These achievements not only elucidate the central role of lactylation in the development and progression of urological malignancies but also establish a theoretical foundation for its use as a novel therapeutic target, advancing research in the field of metabolism-epigenetics crosstalk. However, research on lactylation requires deeper exploration of its molecular mechanisms. The regulatory roles of lactylation are highly complex: within the same disease, lactylation of different proteins can exert distinct effects, while lactylation of the same protein may lead to divergent outcomes across different diseases. Furthermore, BC, RCC, and PCa exhibit significant differences in their pathogenesis and oncogenic mechanisms. Consequently, it is challenging to conduct in-depth analysis and integration of the functions and mechanisms of lactylation across these three distinct malignancies. Future studies are needed to further unravel the intricate regulatory network of lactylation in urological tumors. First, although previous studies have found that non-histone lactylation sites far outnumber those on histones ( Yang Z. et al., 2023 ), research in urological malignancies has predominantly focused on histone lactylation. The role of non-histone lactylation in urological malignancies remains insufficiently explored. Second, several studies suggest that crosstalk often occurs between different PTMs ( Peng and Du, 2025 ; Qu et al., 2025 ), yet the interactions between lactylation and other PTMs—such as acetylation and phosphorylation—in urological malignancies are still unclear. For instance, whether competitive binding occurs between lactylation and acetylation at the histone H3K18 site. Deciphering these cross-regulatory networks is essential for understanding the specificity of lactylation-mediated regulation. Moreover, most current studies have predominantly focused on the tumor-promoting role of lactylation in urological tumors, with only limited evidence suggesting its potential tumor-suppressive functions. Future research should comprehensively investigate the dual roles of lactylation in these malignancies. Finally, it remains unclear whether the oncogenic or tumor-suppressive effects of lactylation are context-dependent. For instance, whether lactylation exerts distinct functions across different tumor types, microenvironmental conditions (e.g., hypoxia levels, lactate concentration), modification targets, and specific modification sites requires further investigation. Challenges in clinical translation are even more pronounced. Most existing prognostic models are based on bioinformatic analyses of public databases and lack independent validation through multi-center, large-sample clinical cohorts. Their applicability across different ethnicities and clinical stages remains unclear, and the potential predictive value of these models still requires confirmation via prospective studies. Although anti-tumor strategies targeting lactylation have shown broad potential, currently validated effective drugs remain very limited, and their safety profiles require further study. Several challenges persist in this field. On one hand, existing HDAC inhibitors, LDHA inhibitors, and similar agents often lack sufficient specificity, potentially affecting normal cellular functions while suppressing tumors. There is an urgent need to develop more selective compounds and systematically evaluate their impact on healthy tissues. Utilizing targeted technologies such as nano-delivery systems and antibody-drug conjugates to achieve precise regulation of tumor cells may represent a critical approach to overcoming this bottleneck ( Dong et al., 2019 ; Maksymova et al., 2025 ; Yu et al., 2024 ). On the other hand, optimizing combination therapy regimens is another key direction. Preclinical studies indicate that lactylation inhibitors combined with immune checkpoint blockers or chemotherapy drugs can produce significant synergistic effects ( Deng J. et al., 2025 ; Wu et al., 2025 ; Liang et al., 2025 ). However, their mechanisms of action, dosing schedules, optimal ratios, and long-term safety profiles still need to be clarified through subsequent clinical trials. Future research requires coordinated breakthroughs in three key areas: technological innovation, mechanistic exploration, and clinical translation. At the technological level, current methods exhibit limited accuracy in detecting low-abundance lactylation, particularly on non-histone proteins. There is an urgent need to develop high-resolution detection tools that combine ultra-sensitive mass spectrometry with highly specific antibodies to improve the precision of lactylation level quantification. Furthermore, integrating lactylomics with metabolomic and transcriptomic data will help construct “metabolism-modification-phenotype” association networks, enabling the characterization of lactylation features in cisplatin-resistant subpopulations in BC and neuroendocrine-differentiated cells in PCa. Mechanistically, future studies should focus on elucidating the spatiotemporal dynamics of lactylation to determine whether temporal or spatial variations in lactylation patterns occur in urological malignancies. Additionally, applying structural biology approaches to decipher the competitive or cooperative relationships between lactylation and other PTMs will significantly deepen our understanding of lactylation’s role in urological malignancies. In terms of clinical translation, multi-dimensional prognostic models must be optimized by incorporating lactylation levels, gene expression profiles, and clinicopathological features to enhance predictive accuracy. Moreover, developing highly selective inhibitors targeting key lactylation-related enzymes or proteins will be essential to minimize off-target effects and improve therapeutic specificity. In summary, significant progress has been made in understanding the role of lactylation in urological malignancies, yet the complexity of its regulatory mechanisms and the challenges in clinical translation require continued exploration. With advancements in technological methods and in-depth mechanistic studies, lactylation is expected to become a novel breakthrough for precision diagnosis and treatment in urological malignancies, providing a solid theoretical foundation and practical basis for improving patient prognosis.