As a glycogenic amino acid, L-serine has various sources, such as an external diet, intracellular synthesis (from the glycolytic intermediate 3-phosphoglycerate and glycine), and cleavage of proteins and phospholipids in vivo (Kishor et al., 2020). Owing to the existence of the blood-brain barrier, L-serine absorbed from the diet cannot meet the needs of the brain and thus must be synthesized in situ (Yoshida et al., 2004). During de novo synthesis, L-serine is converted from 3-phosphoglycerate (3-PG), an intermediate of glycolysis, through a three-step enzymatic reaction, in which 3-phosphoglycerate dehydrogenase (PHGDH) is the first rate-limiting enzyme ( Figure 1a ) (Mattaini et al., 2016; Shen et al., 2021). L-serine, on the other hand, is reversibly catalyzed to glycine and CH2-THF by SHMT1 or SHMT2 in the cytosol or mitochondria, respectively, and participates in one-carbon metabolism and the S-adenosine methionine (SAM) metabolic network through the transfer of one-carbon units ( Figure 1b ) (Locasale, 2013; Mattaini et al., 2016).

Therefore, L-serine is a precursor molecule for the synthesis of many substances, and the metabolism of L-serine includes the synthesis of amino acids, phospholipids, and proteins (Holeček, 2022). First, serine, as the main substrate, plays an important role in protein synthesis (Reeds, 2000). In addition, L-serine mainly synthesizes glycine and cysteine via transsulfuration to participate in the formation of glutathione (GSH), which plays significant roles in redox reactions ( Figure 1c ) (Zhang et al., 2018a; Zhang et al., 2019). Moreover, L-serine is involved in the synthesis of phospholipids and glycolipids, which are important components of cell membranes and highly direct cell differentiation, proliferation, and apoptosis (Murtas et al., 2020). In addition, L-serine is a major carbon unit donor of the folate cycle that produces NADPH, NADH and ATP in the one-carbon metabolic reaction, as well as the main carbon unit donor in the methionine cycle to synthesize adenosine, guanosine, and thymine (Ducker and Rabinowitz, 2017; Kim and Park, 2018), and a methyl donor for protein and DNA synthesis ( Figure 1d ) (Murtas et al., 2020). Collectively, the synthesis and metabolism of serine are summarized in Figure 1 .

In 1992, Hashimoto et al. first reported the presence of large amounts of free D-serine, the optical isomer of L-serine, in mammalian brain tissue (Hashimoto et al., 1992). Later, Schell and Williams et al. found that the distribution of D-serine varied regionally, i.e. it was clearly located in the astrocytoid cell subpopulation (Schell et al., 1995), which also implied that D-serine may be involved in a biosynthetic pathway. Wolosker and colleagues purified serine racemase, which can directly racemate L-serine to form D-serine, and found that multiple properties of SR were similar to those of bacterial racemase, suggesting that the D-amino acid biosynthesis pathway is conserved from bacterial to mammalian brains (Wolosker et al., 1999).

The metabolism of D-serine is catalyzed mainly by D-amino acid oxidase (DAAO) bonding flavin adenine dinucleotide (FAD) ( Figure 1e ) (Pollegioni and Sacchi, 2010). A comparative study of wild-type (WT) and SR-knockout (SR-KO) mice revealed that the SR is involved primarily in D-serine production in the forebrain of mice, and that there might be other D-serine production pathways may be involved in the brain and peripheral organs (Horio et al., 2011). Due to differences in tissue culture and immunocytochemical techniques, there is still no clear conclusion on whether D-serine is distributed in astroglia or neurons, and Coyle et al. have already made a clear discussion on this issue (Coyle et al., 2020); we will not go into the details here.

A study demonstrated that an important rate-limiting factor in maintaining D-serine balance in the brain is L-serine synthesis via the phosphorylation pathway, which is modeled in mice with astrocyte conditions lacking Phgdh. Moreover, D-serine deficiency restricts the function of NMDA receptors (NMDARs) (Yang et al., 2010). D-serine is an endogenous co-agonist of NMDARs and is required to regulate synaptic plasticity and excitatory transmission in the central nervous system (CNS) (Mothet et al., 2000; Panatier et al., 2006). In addition, some studies have proposed the concept of a “serine shuttle” in astrocyte-neuron metabolism, in which D-serine indirectly regulates NMDAR (Bonvento and Bolaños, 2021; Wolosker and Radzishevsky, 2013). Therefore, some studies have shown that the level of D-serine in the host may be related to neurological diseases, such as Alzheimer’s disease, cognitive dysfunction, schizophrenia, depression, and addiction (Holeček, 2022).

However, D-serine has been reported to be nephrotoxic and neurotoxic. For example, astrocytes in primary cultures express SR, synthesize D-serine and acquire A1 (an excitotoxic moiety released from inflammation) reactive astrocyte features (Coyle et al., 2020). Hippocampal synaptic damage in mouse caused by controlled cortical impact resulted in the conversion of D-serine release from neurons to astrocytes, further exacerbating synaptic damage and dysfunction (Perez et al., 2017). On the other hand, D-serine mainly causes dose-related (≥500 mg/kg) nephrotoxicity in rats, manifested as reversible acute tubular necrosis (Okada et al., 2017). However, compared with humans, the ratio of the oral dose to the serum concentration seems to be higher in rats than in humans, making it difficult to directly apply relevant studies to humans (Meftah et al., 2021). In conclusion, L-serine, as a precursor of D-serine synthesis, is involved in the regulation of D-serine level, so the transformation from L-serine to D-serine is of great significance to human health.

As previously mentioned, L-serine participates in complex metabolic networks in the body, so it has the potential to regulate cellular processes such as cell proliferation and immune cell activation by regulating the metabolic microenvironment and nutrient availability. For example, L-serine provides glycine and one carbon unit to effector T (Teff) cells and promotes their proliferation independently of glycolysis (Ma et al., 2017). In addition, L-serine supports cell proliferation and maintains mitochondrial function through ceramide metabolism (Gao et al., 2018). On the other hand, L-serine is catalyzed by serine palmitoyl transferase (SPT) to synthesize sphinganine and eventually generate ceramide, which plays a role in neuronal genesis and survival (Muthusamy et al., 2020). When alanine is the substrate, SPT catalyzes the production of toxic 1-deoxysphinglipids (doxSLs), which may induce neuropathy (Muthusamy et al., 2020).

Interestingly, L-serine regulates growth hormone and corticosterone concentrations, which may be related to its metabolic rhythm (Wu et al., 2019). The concentration of L-serine in cerebrospinal fluid (CSF) decreases with age from a mean of 59 μmol/L at the age of 1 week to a mean of 31 μmol/L at the age of 10 years, suggesting that the demand for L-serine varies with age (van der Crabben et al., 2013). Moreover, L-serine can enhance the circadian phase resetting of mice and humans induced by light, and supplementation with L-serine is helpful for human sleep (Ito et al., 2014). In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the pacemaker that regulates circadian rhythms (Yan et al., 2020). L-serine alters the long-term expression pattern of the SCN clock gene through GABA_A receptors and enhances light-induced phase resetting in mice and humans, so the combination of L-serine and light therapy may help treat circadian rhythm disturbances (Yasuo et al., 2017).

As a potential anti-stress factor, L-serine not only decreases the production of ROS induced by cisplatin (Monroe et al., 2021) but also attenuates the stress response of neonatal chicks (He et al., 2021); accordingly, researchers suspect that L-serine may be an anti-stress factor. Therefore, studies have investigated the effects of L-serine on the behavior of animals exposed to chronic stress, and the results suggest that the oral administration of L-serine reduces the locomotor activity of socially isolated rats (Shigemi et al., 2010). In addition, L-serine can attenuate the stress response of neonatal chicks under acute stress conditions (Kurauchi et al., 2009). Therefore, L-serine may have application value as an anti-stress factor. With respect to the underlying mechanism, a series of studies have shown that L-serine administration attenuates oxidative stress by increasing catalase (CAT), GSH peroxidase (GSH-Px), superoxide dismutase (SOD) and diamine oxidase (DAO) levels while decreasing apoptosis and malondialdehyde (MDA) levels (He et al., 2023; Zhou et al., 2018a; Zhou et al., 2018c). This is achieved mainly by contributing to the methionine cycle (Zhou et al., 2017) and the SIRT1 pathway (Zhou et al., 2018b), inhibiting hypermethylation of promoter associated with GSH synthesis-related genes, and activating the adenosine 5’-monophosphate (AMP)-activated protein kinase (AMPK) pathway (Zhou et al., 2018a). Therefore, L-serine is a relatively effective small molecule for the treatment of oxidative stress with a low risk of side effects ( Figure 2a ).

Obesity is a disease associated with chronic inflammation, oxidative stress, insulin resistance, unbalanced nutrition and other factors (Gasmi et al., 2021). The addition of L-serine to pregnant mice can change the composition of free amino acids in maternal milk and reduce the weight of offspring (Sim et al., 2015). L-serine significantly reduces ingestion and weight gain by reducing the expression of foodborne peptides in aging mice (Zhou et al., 2018c) ( Figure 2b ). However, maternal dietary serine supplementation could improve the nutritional status of sows and their offspring, which might contribute to the increased body weight of offspring (Zhou et al., 2022a). Thus, more experimental studies are necessary to analyze the specific role of serine in obesity.

Additionally, clinical samples revealed that serum L-serine levels were lower in patients with type 2 diabetes and gestational diabetes than in those without (Holm and Buschard, 2019), and L-serine addition reduced blood sugar and improved blood glucose tolerance, thereby reducing the incidence of type 1 diabetes in Non-obese diabetes (NOD) mice (Rotstein et al., 2010) ( Figure 2c ). Moreover, sphingolipid, which is synthesized from L-serine and palmitoyl-CoA (Rotstein et al., 2010), has important functions in regulating insulin folding, secretion, proliferation and apoptosis (Holm et al., 2018). Therefore, the beneficial effect of L-serine supplementation on diabetes may involve regulating the composition of complex sphingolipids ( Figure 2d ), but a more detailed mechanism needs to be further studied. Collectively, L-serine could exert its effects on obesity and diabetes via various potential mechanisms ( Figures 2b–d ).

Inflammation is a complex process of the immune response (Elinav et al., 2013). In addition to controlling infection and promoting tissue repair, hyperinflammation can also cause tissue damage and disease (Reijnders et al., 2020). Therefore, excessive inflammation needs to be controlled by drugs or other clinical methods to avoid tissue damage (Reijnders et al., 2020). However, medications often have side effects and require the supervision of a doctor. Thus, uncovering the potential role of existing natural nutrients in the treatment of inflammatory diseases could provide new directions for safe drug use.

As mentioned above, L-serine has anti-inflammatory effects and has been proved to have certain therapeutic effects on a variety of inflammation-related diseases, such as fatty liver, obesity, and diabetes (Zhang et al., 2021). For example, drugs containing L-serine can be used to prevent and treat fatty liver diseases according to a patent (Lee and Yin, 2011), and L-serine alone further illustrates the potential of L-serine to treat fatty liver disease by reducing alcohol-induced hepatic lipid accumulation and increasing GSH and adenosine methionine levels by increasing homocysteine metabolism in mice and rats (Sim et al., 2015) ( Figure 2e ).

The participation of L-serine in the regulation of signaling pathways can not only relieve stress but also participate in the regulation of the inflammatory response. Studies have shown that L-serine decreases the production of IL-1β, TNF-α, IL-6 and IL-8 through the AMPK and nuclear factor kappa-B (NF-κB) signaling pathways, thereby reducing most of the inflammatory response in the host (Zhou et al., 2018b; Zhou et al., 2018c). Notably, we recently discovered that exogenous L-serine reduces macrophage and neutrophil-mediated lung inflammation in mice infected with P. multocida (He et al., 2019), and the underlying mechanism might be related to the macrophage inflammasome (unpublished data). Besides, this review highlights the great potential of L-serine in counteracting the growing threat of excessive inflammation ( Figures 2f, g ).