Introduction: Connecting Cancer Metabolism to DNA Repair
Cancer cells undergo profound metabolic reprogramming, with the Warburg effect enabling sustained aerobic glycolysis and excessive lactate accumulation even under oxygen-rich conditions. While lactate was once viewed primarily as a metabolic byproduct, it has emerged as an important regulator of cellular signaling through lysine lactylation, a post-translational modification that links metabolism to gene regulation.
At the same time, genomic instability remains one of cancer’s defining characteristics. Most radiotherapy and chemotherapeutic agents eliminate tumor cells by inducing DNA damage, particularly DNA double-strand breaks (DSBs). To survive these treatments, cancer cells rely on highly efficient DNA repair mechanisms.
Yet one critical question has remained unresolved: How does tumor metabolism influence DNA repair and contribute to chemotherapy resistance?
Answering this question requires comprehensive profiling of protein modifications capable of capturing dynamic lactylation events across complex biological systems.
Research Discovery: NBS1 Lactylation Emerges as a Driver of Therapy Resistance
A landmark study published in Nature, titled “NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance,” led by Prof. Changhua Zhang, Prof. Dong Yin, and Prof. Yulong He from Sun Yat-sen University, uncovered a previously unknown mechanism connecting lactate metabolism with DNA repair efficiency.
The researchers demonstrated that lactate promotes homologous recombination (HR)-mediated DNA repair by inducing lactylation of NBS1, a core component of the MRE11-RAD50-NBS1 (MRN) complex responsible for sensing DNA double-strand breaks.
The study identified lysine 388 (K388) as the critical lactylation site on NBS1. Modification at this residue proved essential for MRN complex assembly and for recruiting key HR repair proteins to damaged DNA.
Importantly, reducing lactate production—either through LDHA deletion or pharmacological inhibition with stiripentol—suppressed NBS1 K388 lactylation, impaired DNA repair, and restored sensitivity to chemotherapy.
Together, these findings establish lactate-dependent NBS1 lactylation as a direct molecular bridge between cancer metabolism and treatment resistance, while identifying lactylation inhibition as a promising therapeutic strategy.
Core Breakthrough: PTM BIO’s 4D Lactylation Proteomics Maps the DNA Repair Modification Landscape
Deciphering this regulatory pathway required the ability to comprehensively profile lactylated proteins involved in DNA damage responses.
To systematically investigate lactylation during chemotherapy resistance, the research team employed PTM BIO’s 4D Lactylation Proteomics platform, together with high-resolution LC-MS/MS analysis, to map modification events across resistant tumor samples.
Initial proteomic and untargeted metabolomic analyses revealed that LDHA and lactate were among the most prominently elevated molecules in chemotherapy-resistant gastric tumors, indicating activation of glycolytic metabolism in resistant disease.
Building on these findings, PTM BIO’s lactylation proteomics enabled researchers to identify NBS1 as a critical DNA repair protein undergoing lactylation. Integration of 4D lactylation profiling with protein interaction analysis further uncovered TIP60 as a previously unrecognized lactyltransferase responsible for catalyzing NBS1 K388 lactylation.
Rather than relying solely on candidate-based investigation, the comprehensive modification landscape allowed researchers to connect metabolic alterations with functional DNA repair pathways, transforming global lactylation data into mechanistic insight.
PTM BIO: From Comprehensive Modification Profiling to Mechanistic Validation
In this landmark Nature study, PTM BIO provided an integrated suite of PTMomics technologies and research tools that supported discovery, validation, and mechanistic investigation.
Deep-Coverage Lactylation Profiling
PTM BIO’s optimized 4D lactylation proteomics workflow enabled sensitive detection of low-abundance lactylation events across complex tumor samples, providing comprehensive coverage of DNA repair-related modifications.
High-Confidence Validation
To strengthen mechanistic conclusions, PTM BIO supplied pan-lactylation antibodies, pan-acetylation antibodies, NBS1 K388 site-specific antibodies, and custom antibody solutions, enabling orthogonal validation across biochemical and cellular experiments.
Integrated PTMomics Solutions
By combining discovery proteomics, site-specific validation, and advanced bioinformatics analysis, PTM BIO helped establish a complete experimental workflow from large-scale modification screening to precise mechanistic interpretation.
Scientific Impact: A New Therapeutic Avenue for Overcoming Chemotherapy Resistance
This study significantly advances our understanding of how metabolic reprogramming reshapes DNA repair capacity in cancer.
By demonstrating that lactate-dependent NBS1 lactylation enhances homologous recombination through stabilization of the MRN complex, the research identifies a previously unknown mechanism underlying chemotherapy resistance.
The work also carries important translational implications. Clinical analyses revealed that elevated LDHA expression and NBS1 K388 lactylation correlate with poor prognosis and neoadjuvant chemotherapy resistance in gastric cancer patients, highlighting the pathway’s clinical relevance.
Furthermore, the finding that stiripentol, an LDHA-targeting metabolic intervention, suppresses NBS1 lactylation and sensitizes tumors to DNA-damaging therapies suggests a promising combination strategy for improving treatment outcomes.
More broadly, the study expands the growing landscape of lactylation biology by identifying TIP60 as a new lactyltransferase, further demonstrating how post-translational modification research continues to reveal hidden regulatory mechanisms across precision medicine.
PTM BIO: Empowering Next-Generation PTMomics Research
As a leader in proteomics-driven life science research, PTM BIO is committed to helping researchers decode complex biological regulation through advanced mass spectrometry technologies and integrated PTMomics solutions.
Our capabilities—including 4D Lactylation Proteomics, phosphorylation proteomics, acetylation proteomics, novel acylation profiling, site-specific antibody development, custom antibody generation, and targeted validation—enable researchers worldwide to transform comprehensive molecular profiling into impactful biological discoveries.
From biomarker discovery to mechanistic validation, PTM BIO continues to support cutting-edge research across cancer biology, DNA repair, metabolism, immunology, and beyond.
