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Serine is a non-essential amino acid – the body can synthesise it via the phosphoglycerate dehydrogenase (PHGDH) pathway from the glycolytic intermediate 3-phosphoglycerate. In most tissues, this endogenous synthesis is sufficient to meet demand. Human keratinocytes, however, are an exception: primary keratinocyte research has demonstrated that both extracellular serine supply and endogenous de novo synthesis contribute to keratinocyte proliferation, and that blocking de novo serine biosynthesis with a PHGDH inhibitor reduces proliferation capacity even when extracellular serine is available. Deprivation of serine and glycine simultaneously reduces keratinocyte proliferation and differentiation significantly, with metabolomic profiling confirming this is mediated through depletion of purine nucleotides rather than protein synthesis alone. Human keratinocytes are therefore described as serine and glycine auxotrophs – cells that depend on external supply of these nominally non-essential amino acids to meet the demands of active proliferation. ^[1]

Serine as the Ceramide Synthesis Substrate

Serine’s most mechanistically significant role in skin barrier biology is as the obligatory amino acid substrate for serine palmitoyltransferase (SPT) – the rate-limiting enzyme that initiates the de novo ceramide synthesis pathway. SPT catalyses the condensation of L-serine with palmitoyl- CoA to form 3-ketodihydrosphingosine, the first committed intermediate in sphingolipid synthesis, from which all ceramide classes are ultimately derived. The enzyme strictly requires L-serine – other amino acids cannot substitute. ^[2]

This substrate specificity has a direct clinical implication: serine availability is a genuine upstream constraint on the rate of ceramide production, independent of SPT enzyme expression levels. Research in psoriatic epidermis confirmed that SPT expression inversely correlates with disease severity (PASI score) – the worse the inflammatory state, the lower the SPT expression, and therefore the lower the ceramide synthesis capacity. Acute barrier perturbation triggers a compensatory increase in SPT activity of approximately 35–60% in both the lower and outer epidermal layers, confirming that ceramide synthesis is actively upregulated in response to barrier disruption – and that this upregulation places an increased demand on serine availability precisely when the barrier needs to rebuild. ^{[4] [3]}

The relationship between serine supply and SPT activity is modulated by a ceramide-sensing feedback system. ORMDL proteins form regulatory complexes with SPT and suppress its activity when ceramide levels are adequate – the substrate (serine) and enzyme (SPT) interaction therefore only becomes rate-limiting once this ORMDL brake is released by falling ceramide. This means serine availability is most consequential during active ceramide depletion or barrier repair, when ORMDL-mediated suppression is reduced and SPT activity is at its highest demand. In post-menopausal skin, an additional layer applies: oestrogen decline reduces SPTLC2 expression specifically, which reduces the rate at which serine is consumed for C18-chain ceramide synthesis. Increasing serine availability in this context does not restore the C18 ceramide profile, because the subunit that would use the substrate for the most barrier-relevant chain lengths is the suppressed variable.

Clinical Pearl The same IL-4 and IL-13 cytokines that suppress SPT expression in inflamed skin simultaneously deplete serine availability in keratinocytes through their broader effects on amino acid metabolism. The substrate (serine) and the enzyme (SPT) are both compromised by the same inflammatory environment – and the ORMDL feedback system that normally modulates SPT is also dysregulated by chronic inflammation. The result is a ceramide synthesis failure operating at three points in the same pathway simultaneously: reduced substrate, reduced enzyme expression, and disrupted homeostatic regulation. This is why resolving the inflammatory environment is a prerequisite for meaningful ceramide recovery, not simply a supporting step.

Serine in the Serine–Glycine One-Carbon Metabolism Axis

Serine is also the primary substrate for the enzyme serine hydroxymethyltransferase (SHMT), which converts serine to glycine while simultaneously transferring a one-carbon unit to tetrahydrofolate (THF) for use in nucleotide synthesis and methylation reactions. In keratinocytes, the mitochondrial isoform SHMT2 is particularly important – silencing SHMT2 significantly reduces the proportion of keratinocytes in active cell division (S phase), demonstrating that serine catabolism through this pathway drives the nucleotide availability on which keratinocyte proliferation depends. ^[1]

This is also the pathway through which serine contributes to glycine supply in the epidermis – the SHMT1/2 reaction produces glycine as a co-product of serine catabolism, creating a metabolic link between serine availability and the glycine supply that underpins both keratinocyte proliferation and collagen synthesis. Serine and glycine availability in the epidermis are therefore not independent: restricting dietary serine reduces both the serine substrate pool for SPT and the glycine production rate through SHMT, simultaneously compromising ceramide synthesis, keratinocyte proliferation, and the glycine supply for procollagen assembly in adjacent fibroblasts. ^[1]

Serine as an NMF Component

Free serine is one of the amino acids released by filaggrin proteolysis in the outer stratum corneum, contributing directly to the NMF pool. Alongside glycine, alanine, histidine, glutamine, and arginine, serine was identified in the Miyamoto et al. 2024 196-subject clinical study as one of the six free amino acids most significantly correlated with measured skin hydration values. As a hygroscopic free amino acid within the corneocyte, serine binds water molecules and contributes to the skin’s passive water-retention capacity independently of the extracellular lipid matrix. ^[5]

This dual appearance of serine – as both an NMF humectant within the corneocyte and an SPT substrate for ceramide production in the extracellular lipid matrix – makes it unusual among the amino acids in having concurrent relevance to both hydration systems in the stratum corneum. Most amino acids contribute to one or the other; serine contributes to both through entirely different mechanisms.

Serine and the Differentiation Programme

The keratinocyte differentiation findings from the serine/glycine research carry an additional implication for barrier biology. Serine/glycine-deprived keratinocytes in the research model showed not only reduced proliferation but also reduced expression of late differentiation markers including filaggrin and loricrin – two of the proteins most central to barrier integrity and NMF production. The mechanism involves reduction in α-ketoglutarate, which drives the epigenetic demethylation (H3K27me3 reduction) that normally triggers differentiation programme entry. Serine shortage therefore impairs the differentiation pathway that produces filaggrin, which in turn reduces the NMF pool that serine itself partly constitutes – a self-reinforcing loop with practical consequences for barrier recovery speed after disruption. ^[1]