contributed to drafting and editing of the manuscript. first qualitative and quantitative profile of lysine succinylation in GC. We identified a novel mechanism through which the TCA cycle and pentose phosphate pathway might be regulated through lysine succinylation in their core enzymes. We then examined the potential of using lysine succinylation as a biomarker for GC and successfully developed a succinylation-dependent antibody for the K569 site in Caldesmon as putative biomarker. Finally, we investigated the relationship between the lysine succinylome and lncRNAs, identifying potential crosstalks between two lncRNAs and one succinylation site. These results expand our understanding of the mechanisms of tumorigenesis and provide new information for the diagnosis and prognosis of GC. On a global scale, gastric cancer (GC) ranks as one of the most common malignant tumors and one of the leading causes of cancer death, especially in less developed countries1. In Adjudin 2012, there were approximately 951,600 new GC cases and 723,100 associated deaths around the world1. GC is a complicated disease due to its histological and etiological heterogeneity2 and high tendency for lymph node metastasis (LNM), which remains the most important prognostic factor for GC patients. More than 50% of GC patients have LNM when initially diagnosed, which lead to a 5-year survival rate 30%3. Besides, the prognosis of LNM-negative patients was significantly better than that of positive patients4. Although the number of metastatic lymph nodes is considered the most significant evaluation of overall survival (OS), the negative lymph node count can play important roles of prognostic evaluation and clinical treatment of GC5. Not only in advanced gastric cancer (AGC), LNM in early gastric cancer (EGC) is also a critical factor for assessment of prognosis and therapeutic strategy6. Although decreasing trends in GC incidence and mortality rates have been observed in many countries, significant challenges continue to impede our understanding of GC, especially in the process of LNM. Proteomic and protein functional studies have found that numerous protein candidates may play important roles in the LNM of different cancers7. Recently, based on the rapid development of quantitative proteomic approaches by tandem mass spectrometry (MS/MS), differential protein expression levels have been revealed in various tumors8,9,10,11,12. This may help identify feasible protein candidates as novel diagnostic biomarkers PSTPIP1 and prognostic targets. Protein post-translational modifications (PTMs) have also been shown to play important roles in regulating protein functions13, with specific PTMs on certain substrate residues diversifying and regulating the cellular proteome14. Multiple well-known modifications including acetylation15 and SUMOylation16, as well as several novel PTMs including succinylation17 and malonylation18, were recently investigated using MS/MS, utilizing high-quality antibodies against PTMs and biochemistry methods. These PTMs widely exist in eukaryotic and prokaryotic organisms19. Moreover, PTMs are deeply involved in human diseases20 including malignant tumors21,22, and proteins that mediate epigenetic regulations through histone acetylation and methylation are proven to be associated with the progression of cancers23. Furthermore, O-glycosylation changes in the serum of GC patients suggest that it, too, might correlate with GC tumorigenesis24. Among these PTMs, lysine succinylation (Ksucc) is a novel PTM first identified in em Escherichia coli /em 17. As an evolutionarily conserved modification existing in multiple species25,26,27,28,29,30,31,32, it may affect various cellular functions including the tricarboxylic acid (TCA) cycle and fatty acid metabolism33. Therefore, Ksucc may play significant roles in the regulation of cellular metabolism, yet its role in cancer has not been explored. Tumor cells make complicated metabolic alterations characterized by changes in multiple metabolic pathways such as energy production Adjudin and biosynthetic processes34, and protein Adjudin acetylation, a well-known PTM, is known to regulate metabolism in pancreatic cancer22. Based on this, we hypothesized that Ksucc might play a role in cancer by regulating important cellular metabolic pathways. It has been accepted that the pathogenesis of GC involves multi-dimensional aspects due to the complexity and heterogeneity of the disease. Recently,.