In this study, we analyzed the metabolites in the serum of NSSI-naïve patients and compared them with those of healthy controls to identify differential metabolites. A total of 235 differential metabolites were identified in the cationic mode, with 133 being up-regulated and 102 down-regulated. In the anionic mode, 66 differential metabolites were identified, including 14 up-regulated and 52 down-regulated metabolites. Through qualitative and quantitative analyses of these differential metabolites, combined with specific sample grouping, we obtained significant differential fold changes in the metabolite levels between the NSSI group and the normal group.
In the positive ionic mode, up-regulated differential metabolites included glycerophospholipid analogs (PE-NMe, PA), glycerol ester analogs (1-Palmitoleoyl-2-myristoleoyl-sn-glycerol), heterocyclic compounds (1-(7-Methyl-2,3-dihydro-1H-pyrrolizin-5-yl)propan-1-one), amino acids (L-argininyl-L-threonyl-L-isoleucine, valine-isoleucine-lysine, L-asparagine-L-glutamine-L-glutamine), neonicotinoid acetate, hormones testosterone decanoate, phosphatidic acid PA (22:1(13Z)/20:2(11Z,14Z)), benzene and its derivatives mibefedil, β-ecdysone. Down-regulated differential metabolites included carnitine C14:3, nicotinamide, and 4-hydroxynonenal acetylene.In the negative ion mode, up-regulated differential metabolites were succinate semialdehyde, N-(2-furyl)glycine, 9,10-epoxyoctadecanoic acid. Down-regulated differential metabolites included verapamil, phenylacetylglutamine, histidine-lysine-threonine, reserpinephrine, 4-hydroxy-2-adrenal, steroid hormones, p-coumaral, bromfenac, o-hydroxybenzoic acid, ciprostatin, dihydroferrocine, cyclic prostaglandins, 24,25-diacetylturfoside, isohydroxycholic bile acid, 6-dehydro-L-mannose, 1-O-hexadecyl-2-oleoyl-sn-glycero-3-phosphorylcholine.
These findings suggest that the identified differential metabolites play a significant role in distinguishing NSSI patients from healthy controls and may have potential as diagnostic biomarkers.
In this study, we conducted a comprehensive KEGG pathway annotation of differential metabolites identified from the serum of NSSI-naïve patients and healthy controls. A total of 311 KEGG pathways were obtained, comprising 158 positive ion and 153 negative ion pathways. The KEGG-enriched gene pathway analysis revealed that the pathways related to the differential metabolites between the NSSI and NC groups were primarily associated with the synthesis and secretion of parathyroid hormone, tyrosine metabolism, pentose phosphate pathway, nicotinic acid and nicotinamide metabolism, metabolic pathways, carbohydrate metabolism, butyrate metabolism, cofactor biosynthesis, amino acid biosynthesis, alanine, aspartate and glutamate metabolism, arginine and proline metabolism, arachidonic acid metabolism, alpha-linolenic acid metabolism, retrograde endocannabinoid signaling, bile secretion, 2-carboxylic acid metabolism, linoleic acid metabolism, glycerophospholipid metabolism, carbon metabolism, and choline metabolism in cancer.
To identify the key pathways most strongly associated with the differential metabolites, we performed a KEGG analysis of these metabolites. Based on the results of the enrichment analysis, we selected the top 20 HMDB primary pathway maps with significant P values for display. By considering both the Rich Factor value and P value, we filtered out the key pathways with significant enrichment and the highest degree of enrichment. The results are presented as follows: in the positive ion mode, aromatase deficiency, 17-β hydroxysteroid dehydrogenase III deficiency, nadolol pathway of action, timosartan pathway of action, and androstenedione pathway of action were identified. In the negative ion mode, key pathways included androgen and estrogen metabolism, α-linolenic acid and linoleic acid pathway, and nicotinic acid and nicotinamide pathway.
These findings underscore the potential role of these pathways in the pathophysiology of NSSI and may provide insights into the underlying mechanisms contributing to the development of NSSI behaviors. Further research is warranted to validate these pathways and explore their potential as therapeutic targets or diagnostic markers for NSSI.
In this study, the gene pathways enriched with differential metabolites in the NSSI patient group compared to healthy controls primarily involved tyrosine metabolism, alanine, amino acid biosynthesis, glutamate and aspartate metabolism, and proline and arginine metabolism. Significant differential fold changes in metabolite levels between the NSSI group and the normal group revealed up-regulation of amino acids (L-arginyl-L-threonyl-L-isoleucine, valine-isoleucine-lysine, and L-asparagine-L-glutamine-L-glutamine) in the positive ionic mode, and down-regulation of phenylacetylglutamine and histidine-lysine-threonine in the negative ionic mode. ROC curves were plotted based on the relative abundance of each differential metabolite in the NSSI group samples, identifying metabolites with an AUC greater than 0.8: glycine, phenylalanine, asparagine, aspartic acid, threonine, histidine, tyrosine, arginine, isoleucine, proline, N-acetylthreonine, glutamine, proline-arginine, organic acids and their derivatives, cyclic propylene, glycerophospholipids, fatty acylcarnitines, geldanamycin, and cycloprostene. These substances are crucial in distinguishing NSSI patients from healthy controls and exhibit high predictive power.
This study investigates the potential link between poor emotion regulation in patients with non-suicidal self-injury (NSSI) and disturbances in amino acid metabolism. It has been established that poor emotion regulation is a core process behind NSSI, and cognitive and emotion regulation deficits are associated with NSSI [10]. Some studies have suggested that disorders of amino acid metabolism are related to mood regulation and cognitive dysfunction [11–13]. Guo Xiangjie et al. found that the guanylate cycle, glutamate metabolism, and purine metabolism play a crucial role in the pathogenesis of bipolar disorder in adolescents with NSSI (31 cases) versus adolescents without NSSI (52 cases) and in a controlled study of adolescents in a healthy group (10 cases)[14]. Amino acids are the basic building blocks of proteins, which can affect the individual's nervous system, thereby impacting the cognitive functions of the body [15]. The NSSI patients in this study had abnormalities in glutamine, an amide of glutamic acid. It was also found that the Alzheimer's disease patient group and the amnestic mild cognitive impairment group had significant differences in amino acid metabolites from the normal control group. Other studies suggest that abnormalities in amino acid metabolism may be associated with these cognitive impairment conditions [16]. Glutamate, an excitatory neurotransmitter closely related to cognitive function [17], is involved in neuronal messaging in the brain and plays an important role in learning and memory processes. Therefore, abnormalities in amino acid metabolism may affect the function of glutamate, leading to cognitive function impairment. Tyrosine metabolites were downregulated in NSSI patients in this study. The amino acid L-tyrosine is a biochemical precursor of catecholamines, dopamine, and norepinephrine. Under appropriate circumstances, tyrosine supplementation can increase dopamine and norepinephrine levels in the brain [18], while low doses of dopamine can improve self-injurious behavior [19]. Another study directly found a strong relationship between suicide in depression and low levels of tyrosine [20–21]. These findings deepen our understanding of the role of abnormal amino acid metabolism in abnormal cognitive functioning in NSSI and provide potential directions for future treatment strategies.
Numerous studies have demonstrated an association between lipid metabolism and suicidal behavior, as well as adolescent depression [22–23]. The present study's results indicate a significant differential fold change in the quantitative information of metabolites between the NSSI group and the normal group. Differential metabolites that were up-regulated in the positive ion mode include glycerophospholipids, glycerol esters, and phosphatidic acid PA (22:1(13Z)/20:2(11Z,14Z)). Among the biological markers measured in this study were glycerophospholipids (1-O-Hexadecyl-lyso-sn-glycero 3-phospho choline) and fatty acylcarnitines (Carnitine C18:3, Carnitine C10:2). Analysis of KEGG-enriched gene pathways revealed that glycerophospholipid metabolism was an enriched gene pathway associated with differential metabolites between the NSSI and NC groups. Based on Rich Factor values and P values, we identified α-linolenic acid and linoleic acid metabolism as one of the key pathways with significant and highest enrichment. Elevated lipid levels may contribute to NSSI behavior by promoting oxidative stress, which subsequently leads to NSSI behavior. Oxidative stress is characterized by an imbalance between intracellular oxidants and antioxidants, potentially leading to cellular damage and inflammatory responses. Consequently, increased lipid levels may further influence the occurrence of NSSI behaviors by exacerbating oxidative stress. These findings suggest that lipid metabolism may play a crucial role in the development of abnormalities in mood regulation in NSSI.
Niacin and nicotinamide metabolic pathways emerged as pivotal in non-suicidal self-injury (NSSI) patients compared to healthy controls. Nicotinamide, a down-regulated differential metabolite, has been shown to support NAD + levels. By supplementing its reduced form of NADH or NAD + precursors such as nicotinamide riboside, nicotinamide mononucleotide, nicotinamide, and nicotinic acid, a potent neuroprotective therapy that enhances cognition can be achieved[24]. NAD + is fundamental to cellular energy metabolism, produced by the TCA cycle through the electron transport chain (ETC), essential for oxidative phosphorylation to generate ATP[25]. Fatty acyl carnitines (Carnitine C18:3, Carnitine C10:2) were among the biological markers measured in NSSI patients. Carnitine, involved in fat metabolism, aids in converting fat into energy[26]. Studies have reported carnitine's positive impact on treating geriatric depression, Parkinson's disease, and Alzheimer's disease, alleviating depressive symptoms, and enhancing patient quality of life[27]. These findings suggest cognitive abnormalities in NSSI patients may be linked to energy metabolism disturbances. Given their roles in energy metabolism, niacin, nicotinamide, and carnitine could potentially restore cognitive function in NSSI patients. Understanding these roles might inform treatment strategies for cognitive dysfunction in NSSI patients and guide future therapeutic explorations.
In this study, we identified arachidonic acid metabolism as a key metabolic pathway implicated in non-suicidal self-injury (NSSI). Specifically, cycloprostenol emerged as a crucial metabolite in distinguishing NSSI patients from healthy controls, demonstrating the highest predictive power. Arachidonic acid facilitates the synthesis of prostaglandins via metabolic pathways involving cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 enzyme (CYP) [28]. These pathways contribute to vasodilatory and antiplatelet aggregation functions. The observed metabolic dysregulation might underlie repetitive self-cutting behaviors seen in NSSI.
In our investigation, choline surfaced as a differential metabolite between NSSI patients and healthy individuals. As an essential nutrient, choline plays a pivotal role in brain development and genomic epigenetic modifications. It modulates neuronal gene expression, methylation, and activity, preserving the structural and functional integrity of cell membranes [29]. Furthermore, choline governs cholinergic neurotransmission by facilitating acetylcholine synthesis, thereby impacting neural signaling [30]. Its functions encompass regulation of biological processes, including histone modification, DNA methylation, and modulation of proteins critical for learning and memory. Through these mechanisms, choline significantly influences nervous system functionality, notably in learning and memory processes [30]. Cognitive deficits observed in NSSI patients might be linked to altered choline metabolism.
In summary, patients with NSSI exhibit distinct metabolic profiles characterized by alterations in various pathways, including parathyroid hormone synthesis and secretion, tyrosine metabolism, pentose phosphate pathway, nicotinic acid salts and nicotinamide metabolism, carbohydrate metabolism, butyrate metabolism, cofactor biosynthesis, amino acid biosynthesis (such as alanine, aspartate, glutamate, arginine, and proline metabolism), arachidonic acid metabolism, alpha-linolenic acid metabolism, retrograde endorphin signaling, bile secretion, 2-carboxylic acid metabolism, linoleic acid metabolism, glycerophospholipid metabolism, carbon metabolism, and choline metabolism. Notable metabolites differentiating NSSI patients from controls include phenylalanine, glycine, aspartic acid, asparagine, threonine, histidine, tyrosine, arginine, isoleucine, proline, N-acetylthreonine, glutamine, and others. These findings offer novel insights into NSSI etiology and may guide future therapeutic approaches. A primary limitation is the study's small male cohort and its focus on Tai'an City residents. Future work will aim to enlarge the cohort and assess metabolite changes pre- and post-medication in NSSI patients to deepen our understanding of these metabolic influences on NSSI behaviors.