Can Lactylation Antibodies Reveal New Mechanisms of Tumor Resistance to Ferroptosis?

I. How Does Protein Lactylation Participate in Cell Fate Regulation?

Protein lactylation is a newly discovered post-translational modification characterized by the covalent attachment of a lactate molecule to a protein lysine residue, catalyzed by lactyltransferases. Initially identified on histones, this modification is believed to connect cellular metabolic status with gene expression regulation. Recent studies indicate that lactylation modifications are widespread in non-histone proteins and participate in regulating various cellular biological processes. In the tumor microenvironment, due to the Warburg effect, cancer cells typically exhibit enhanced glycolytic activity, leading to substantial lactate accumulation, which provides an abundant substrate source for protein lactylation.

Ferroptosis, an iron-dependent, lipid peroxidation-driven form of regulatory cell death, shows significant potential in cancer therapy. However, tumor cells often resist ferroptosis through multiple mechanisms, limiting its therapeutic efficacy. Recent research discovered that in lung adenocarcinoma, ferroptotic stress can induce lactate accumulation, which in turn regulates the function of key proteins through specific lactylation modifications, forming a negative feedback regulatory loop. This finding provides a new perspective for understanding tumor drug resistance mechanisms.

II. How Does Ferroptosis Induce Lactylation Modification?

Studies show that treatment with ferroptosis inducers significantly increases intracellular lactate levels in lung adenocarcinoma cells. Using untargeted metabolomics analysis and screening against an endogenous metabolite library, researchers confirmed that ferroptosis triggers metabolic reprogramming, prompting cells to enhance glycolysis, leading to substantial lactate production. Further experiments demonstrated that adding exogenous lactate significantly enhanced cell resistance to ferroptosis inducers, reduced lipid peroxidation levels, increased the glutathione to oxidized glutathione ratio, and boosted antioxidant capacity.

Western blot analysis using pan-lactylation antibodies revealed a significant increase in global protein lactylation levels after ferroptosis induction. Through lactylome analysis, researchers identified that the lactylation modification at the K11 site of Small Ubiquitin-like Modifier 2 (SUMO2) showed the most significant change. This site is highly evolutionarily conserved and specifically expressed in lung cancer tissues. The development of a specific anti-SUMO2-K11la antibody provided a crucial tool for in-depth study of the functional significance of this modification.

III. How Does SUMO2-K11 Lactylation Regulate Ferroptosis Sensitivity?

To investigate the functional significance of SUMO2-K11 lactylation, researchers constructed a SUMO2-K11R point mutation cell line using gene editing technology. Functional experiments showed that compared to wild-type cells, K11R mutant cells were more sensitive to ferroptosis inducers, with a significantly lower half-maximal inhibitory concentration. Lipid peroxidation assays indicated increased lipid reactive oxygen species levels, elevated malondialdehyde content, and a decreased glutathione to oxidized glutathione ratio in the mutant cells. Electron microscopy further confirmed that K11R mutant cells exhibited more typical ultrastructural features of ferroptosis.

Clinical correlation analysis in 140 lung adenocarcinoma patient tissues showed that high SUMO2-K11la expression was associated with low expression of the lipid peroxidation marker 4-hydroxynonenal. Survival analysis indicated that patients with high SUMO2-K11la expression had significantly shorter overall survival, and it still predicted poor prognosis in patients receiving postoperative chemotherapy. These results suggest that SUMO2-K11la not only participates in the molecular mechanism of ferroptosis resistance but may also serve as a prognostic biomarker.

IV. What is the Specific Molecular Mechanism by Which Lactylation Affects Ferroptosis?

Mechanistic studies revealed that SUMO2-K11 lactylation affects ferroptosis sensitivity by regulating the stability of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4). ACSL4 is a key executor of ferroptosis, responsible for catalyzing the esterification of polyunsaturated fatty acids, promoting the generation of lipid peroxidation substrates. Researchers found a direct interaction between SUMO2 and ACSL4, and SUMO2-K11 lactylation could weaken this interaction.

Further experiments confirmed that the K500 site of ACSL4 can undergo SUMOylation, and SUMO2-K11 lactylation inhibits ACSL4 SUMOylation, thereby promoting its degradation via the ubiquitin-proteasome pathway. Lipidomics analysis showed increased levels of peroxidation-susceptible phosphatidylethanolamine species in SUMO2-K11R mutant cells. These results collectively indicate that SUMO2-K11 lactylation inhibits the ferroptosis process by disrupting ACSL4 stability and reducing the synthesis of pro-ferroptotic lipids.

V. What is the Application Value of Lactylation Antibodies in Research?

Lactylation antibodies, as key tools for detecting lactylation modifications, played a vital role in this study. Pan-lactylation antibodies can be used for initial screening of changes in lactylation levels, while site-specific lactylation antibodies can precisely detect the lactylation status of specific proteins. The development and application of these antibodies provide a technical foundation for in-depth research into the biological functions of lactylation modifications.

As understanding of lactylation deepens, lactylation antibodies will demonstrate greater value in mechanism research, biomarker development, and drug screening. By establishing standardized lactylation detection methods, researchers can more systematically explore the role of lactylation modifications in cancer and other diseases, providing a theoretical basis for developing new therapeutic strategies.

VI. Which Manufacturers Provide Lactylation Antibodies?

Hangzhou Start Bio-tech Co., Ltd.'s self-developed "L-Lactyl Lysine Rabbit Polyclonal Antibody" is an epigenetic research tool characterized by high modification specificity, broad recognition capability, and excellent affinity. This product is ideal for emerging frontier research in metabolism and epigenetics, gene expression regulation, and disease mechanism exploration.

Product Core Advantages:

·       High Modification Specificity & Broad Recognition Capability: Cross-validated with modified/unmodified peptides, it precisely recognizes L-lactylation modifications occurring on lysine residues, with almost no cross-reactivity to other common acylations (e.g., acetylation, crotonylation). Its polyclonal nature enables recognition of lactylation across different protein backgrounds, offering wide coverage.

·       Excellent Affinity & Inter-batch Stability: The product exhibits high affinity, effectively enriching and detecting endogenous lactylated proteins. Strict serum pool management and purification processes ensure high performance consistency across different batches, providing reliable support for long-term research projects.

Suitable Key Application Scenarios:
This product is an ideal tool for conducting the following research:

·       Metabolite Sensing & Signal Transduction Research: For exploring how lactate acts as a signaling molecule to regulate cellular function by inducing protein lactylation, linking cellular metabolism to the epigenetic state.

·       Immune & Inflammatory Response Regulation: For studying the role of lactylation in immunometabolic reprogramming during processes like macrophage polarization and in the tumor microenvironment.

·       Gene Expression & Chromatin Regulation: For identifying lactylation sites on histones and studying their novel functions in transcriptional activation and chromatin dynamics.

·       Disease Mechanism & Biomarker Discovery: For exploring aberrant protein lactylation modifications and their pathophysiological significance in cancer, metabolic diseases, and infectious diseases.

Professional Technical Support: We provide detailed product technical documentation, including specificity validation data, experimental protocols for various application platforms, a recommended target list, and professional technical consultation, fully committed to assisting customers in achieving leading discoveries in the rapidly evolving field of metabolic epigenetics.

Hangzhou Start Bio-tech Co., Ltd. is always dedicated to providing high-quality, high-value biological reagents and solutions for global innovative pharmaceutical companies and research institutions. For more details about the "L-Lactyl Lysine Rabbit Polyclonal Antibody" or to request a sample test, please feel free to contact us.

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