IngredientsPhosphatidylglycerol (PG) is a member of the glycerophospholipid class of molecules — specifically a phosphoglyceride. It is defined chemically as a phosphoglyceride having a phosphoryl glycerol head group. The general structure consists of a L-glycerol 3-phosphate backbone ester-bonded to either saturated or unsaturated fatty acids on carbons 1 and 2, with the head group substituent glycerol bonded through a phosphomonoester.
Phosphatidylglycerol in the physiological pH range possesses a permanent negative charge, which distinguishes it from electrically neutral phospholipids such as phosphatidylcholine and phosphatidylethanolamine. Phosphatidylserine and phosphatidylglycerol carry a negative net charge at neutral pH 7.
Phosphatidylglycerol exists in numerous molecular species distinguished by their acyl chain composition. The dominant naturally occurring species in human pulmonary surfactant is 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG) — also written palmitoyl-oleoyl-phosphatidylglycerol. The second most abundant surfactant lipid class is phosphatidylglycerol (PG), with palmitoyl-oleoyl phosphatidylglycerol (POPG) as the dominant molecular species. Other naturally occurring and synthetic forms include dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidylglycerol (DMPG), and dioleoylphosphatidylglycerol (DOPG). Phosphatidylglycerol may be either a naturally-occurring or a synthetic compound.
Phosphatidylglycerol (PG) is a ubiquitous membrane phospholipid synthesized by a pathway shared in prokaryotes and eukaryotes. In biological systems, PG is synthesized through the CDP-diacylglycerol pathway, a critical metabolic route for many phospholipids. This pathway primarily occurs in the endoplasmic reticulum (ER) and the mitochondria in eukaryotic cells, as well as in plastids in plants.
In commercial and research settings, PG is available in the following preparations:
Phosphatidylglycerol is found across all domains of life and is therefore not confined to any single botanical or zoological source. Its distribution is highly tissue- and organism-specific.
Phosphatidylglycerol is a glycerophospholipid found in pulmonary surfactant and in the plasma membrane where it directly activates lipid-gated ion channels. Surfactant phospholipids account for 80–85% of pulmonary surfactant lipids, including phosphatidylcholine (PC, accounting for about 80%); phosphatidylglycerol (PG, accounting for about 7–15%); and small quantities (accounting for approximately 5% each) of phosphatidylinositol (PI), phosphatidylethanolamine (PE), and phosphatidylserine (PS). Earlier work on pulmonary surfactant composition confirmed that surfactant contained approximately 11.0–11.2% phosphatidylglycerol as a percentage of total phospholipid phosphate.
Notably, PG is concentrated at extraordinarily high levels within the alveolar hypophase. The anionic phospholipids phosphatidylglycerol (PG) and phosphatidylinositol are minor constituents (∼2–10% of total phospholipid) of the pulmonary surfactant complex, but their concentration within the alveolar hypophase is extraordinarily high (∼5–10 mg/ml for PG and ∼2 mg/ml for PI) and greatly exceeds that for any other tissue or mucosal surface.
Phosphatidylglycerol is a vital part of the cell membrane of anaerobic bacteria, playing a crucial role in maintaining the fluidity and structural integrity of the bacterial membrane, which is essential for the proper functioning of the cell. The membrane of Gram-negative bacteria is composed of 70–80% of phosphatidylethanolamine (PEA) and 20–25% of negatively charged lipids, such as phosphatidylglycerol (PG) or cardiolipin (CL), whereas the membrane of Gram-positive bacteria are formed mainly by anionic lipids, such as 70% of PG, 12% of PEA, and 4% of CL.
Phosphatidylglycerol is a crucial phospholipid present in plant cells, primarily residing within thylakoid membranes where photosynthesis, the vital process for plant life, takes place. PG plays a pivotal role in the photosynthetic process by participating in the electron transport chain. It acts as a cofactor for several key proteins involved in the conversion of light energy into chemical energy, allowing for the production of ATP and NADPH during photosynthesis. PG is also involved in the organization and stabilization of photosynthetic pigments, including chlorophyll, in the thylakoid membranes.
Research in plant genetics has demonstrated that PG biosynthesis is required for embryo development and chloroplast biogenesis, as well as the development of thylakoid membranes and the maintenance of membrane structures in mitochondria.
Phosphatidylglycerol constitutes a minor component of most animal cell membranes, typically comprising less than 5% of total phospholipids, though its levels are typically less than 1% in the inner mitochondrial membrane (IMM). In animal mitochondria, PG primarily functions as a critical precursor for cardiolipin (CL) biosynthesis, where it condenses with CDP-diacylglycerol via cardiolipin synthase (CLS1) to form immature CL, which is subsequently remodeled by tafazzin to yield mature CL essential for assembling respiratory chain supercomplexes.
Phosphatidylglycerol, as a discrete isolated compound, has no documented traditional or ethnobotanical history of intentional human use. Unlike many other dietary supplement ingredients derived from medicinal plant traditions, PG was not identified as a distinct biochemical entity until the twentieth century, and its presence in food and biological materials was not associated with any named or codified therapeutic system.
The earliest scientific recognition of phosphatidylglycerol as a significant biological lipid emerged from pulmonary biochemistry research in the 1960s and 1970s. Seminal investigations by Hallman and Gluck in the mid-1970s established PG as an important component of lung surfactant and as a marker of fetal lung maturity in amniotic fluid. A chronicle of findings by physiologists, biochemists, and surface chemists working on pulmonary surfactant led to physicochemical studies establishing criteria for evaluating surface tension measurements. This work was foundational to its subsequent medical applications. The molecule therefore has a scientific rather than traditional therapeutic history.
Phosphatidylglycerol is formed via a complex sequential pathway whereby phosphatidic acid (PA) is first converted to CDP-diacylglyceride by the enzyme CDP-diacylglyceride synthase. The activated phosphatidyl group is then transferred to the sn-1 hydroxyl group of glycerol-3-phosphate to yield phosphatidylglycerophosphate, which subsequently is dephosphorylated to phosphatidylglycerol (PG).
Synthesis of phosphatidic acid (PA) by acylation of glycerol-3-phosphate is the initiating event in phospholipid biosynthesis in both prokaryotic and eukaryotic organisms. The next step is the conversion of PA into CDP-DAG, the central liponucleotide intermediate. In bacteria, CDP-DAG is the precursor for the biosynthesis of all the major phospholipids including PG, CL, PS, and PE.
One of the most important metabolic roles of PG is serving as the immediate precursor for cardiolipin (CL) synthesis. Phosphatidylglycerol is one of the precursors for the production of cardiolipin, phosphatidylinositol, and phosphatidylserine. The mechanism by which PG is converted to CL differs between prokaryotes and eukaryotes: in prokaryotes, PG and a phosphatidyl moiety from a second PG are condensed to CL, whereas in eukaryotes, PG and CDP-diacylglycerol are used as substrates for CL formation.
In eukaryotes (yeasts, plants, and animals), the biosynthetic pathway passes through the common intermediate phosphatidic acid, which is imported from the endoplasmic reticulum and transported to the inner mitochondrial membrane by certain protein complexes at contact sites between the two membranes. The first committed step in biosynthesis is formation of phosphatidylglycerol phosphate as an intermediate for subsequent production of the precursor phosphatidylglycerol.
Cardiolipin, in turn, is critical for mitochondrial function. Cardiolipin increases the efficiency of electron flow and ATP/ADP exchange by associating with the major proteins of the mitochondrial respiratory chain. CL is also required for the electron transport chain super-complex formation, maintenance of cristae morphology, mitophagy, and facilitating mitochondrial fission/fusion.
Pulmonary surfactant lipids together with pulmonary surfactant proteins facilitate breathing by reducing surface tension of the air-water interface within the lungs, thereby preventing alveolar collapse and the mechanical work required to breathe. Phosphatidylglycerol (PG) forms about 11% of the lipids in the surfactant; it has unsaturated fatty acid chains that fluidize the lipid monolayer at the interface. By fluidizing the primarily DPPC-rich monolayer, PG enables the surfactant film to rapidly re-spread during exhalation, restoring uniform coverage of the alveolar surface.
A major area of contemporary research on PG concerns its capacity to suppress innate immune inflammatory signaling. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), are present within the alveoli at very high concentrations, and exert anti-inflammatory effects by regulating multiple Toll-like receptors (TLR2/1, TLR4, and TLR2/6) by antagonizing cognate ligand-dependent activation.
Two minor anionic phospholipids present in the pulmonary surfactant complex — POPG and phosphatidylinositol (PI) — antagonize the cognate ligand activation of TLRs 2 and 4. The lipids block recognition of activating ligands by the TLRs, either directly or via the TLR4 coreceptors CD14 and MD2. Antagonism of TLR activation results in inhibition of the initiating step of the pro-inflammatory signaling pathways. Evidence for this mechanism of action comes from direct binding studies between CD14 and MD2 with POPG and PI.
POPG and PI inhibit inflammatory responses induced by multiple Toll-like receptors (TLR2/1, TLR3, TLR4, and TLR2/6) by interacting with subsets of multiprotein receptor components. The structural requirements for this TLR antagonism are partially defined: simple analogs of POPG harboring polar headgroup modifications can be effective antagonists of the activation of TLR4 and TLR2. The relative plasticity of the structural requirements for inhibition of TLRs raises the possibility that new POPG-like molecules can be designed with higher specificity for individual TLRs and improved biological half-lives.
The antiviral activity occurs by phospholipid binding to the viruses with high affinity and blocking their attachment to plasma membrane receptors on epithelial cells. This is a mechanistically distinct action from the TLR antagonism pathway and applies to multiple viruses. Pulmonary surfactant lipids such as phosphatidylglycerol and phosphatidylinositol participate in the pulmonary host defense and modify immune responses. Emerging data have shown that pulmonary surfactant lipids modulate the inflammatory response and antiviral effects in some respiratory viral infections.
The minor pulmonary surfactant phospholipid POPG antagonizes the proinflammatory actions of M. pneumoniae, Pam3Cys, and MALP-2 by reducing the production of arachidonic acid (AA) metabolites from macrophages. The effect of POPG was specific, insofar as saturated PG, and saturated and unsaturated phosphatidylcholines did not have significant effect on M. pneumoniae-induced AA release. These data demonstrate that POPG suppresses this pathogen-induced response.
At the molecular level, analysis of COX-2 expression showed a dose-dependent increase in COX-2 protein level in Mycoplasma pneumoniae-treated macrophages, and the addition of POPG almost completely reversed the COX-2 level to that of unchallenged macrophages. There was a 20-fold increase in COX-2 protein level in macrophages infected at a multiplicity of infection of 5, and this increase was inhibited 90% by treatment with POPG.
Natural lecithin contains other phospholipids such as phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylglycerol (PG), and lysolecithin (LPC). Some of these minor components are bioactive, for example, the negatively charged molecules PS and PG. The permanent negative charge of PG at physiological pH governs its interactions with membrane proteins, cell-surface receptors, and co-receptors of innate immunity.
The most extensively validated clinical application of phosphatidylglycerol is as a biomarker — measured in amniotic fluid — of fetal lung maturity prior to delivery. Its presence (>0.3) in the amniotic fluid of the newborn indicates fetal lung maturity. Phosphatidylglycerol in amniotic fluid is the second important component of lung surfactant phospholipids and may be clinically useful in assessing fetal lung maturity in utero.
Evidence strength: Strong (multiple clinical cohort studies). The contents of phosphatidylglycerol and phosphatidylcholine phosphorus in amniotic fluid (10,000 × g pellets) were studied as predictors of fetal lung maturity; the presence of phosphatidylglycerol predicted the absence of neonatal respiratory distress syndrome with 99% probability. In a study of 159 transabdominal amniotic fluid samples, the presence of phosphatidylglycerol indicated a 98% prediction rate for absence of respiratory distress syndrome with 1.8% false-positive results corrected to 0%.
Phosphatidylglycerol and the lecithin/sphingomyelin (L/S) ratio were determined, and the shake test was performed, as indicators of fetal lung maturity, in more than 600 patients. In that study, phosphatidylglycerol determination had a false positive rate of 1.8% and a false negative rate of 26.9%. Phosphatidylglycerol determination is an accurate predictor of fetal lung maturity, and predicts lung immaturity more correctly than do the L/S ratio and the shake test.
PG also appeared earlier in gestational development than the L/S ratio in a large study: in a study of 766 amniotic fluids collected from pregnancies between 26 weeks and term, PG was identified in a greater proportion than was a mature L/S ratio at all gestational ages between 28 and 38 weeks regardless of the underlying pregnancy complication. The early appearance of PG was particularly striking in amniotic fluids obtained after preterm rupture of membranes. Since PG has been previously shown to be a useful indicator of the risk of neonatal respiratory distress syndrome, its appearance before a mature L/S ratio suggests it offers a considerable advantage in the management of high-risk obstetric problems.
An important clinical advantage is PG's robustness in contaminated samples. PG may characterize surfactant maturity in samples of amniotic fluid contaminated with blood or meconium as well as specimens collected from the vagina in cases of premature rupture of membranes. This contrasts with the L/S ratio, which has been reported to be inadequate as a predictor of fetal surfactant maturity in many complicated obstetric cases, particularly in patients with diabetes, and is also unreliable when the sample contains blood or meconium.
PG is a recognized, physiologically essential component of the natural and animal-derived surfactant preparations used in clinical surfactant replacement therapy (SRT) for neonatal respiratory distress syndrome (RDS). Several randomized clinical trials have documented a beneficial effect of surfactant replacement in established neonatal respiratory distress syndrome (RDS). These results have been obtained with surfactant isolated from animal lungs or human amniotic fluid. Treatment with exogenous natural surfactant usually reverses the clinical course of severe RDS, reduces the incidence of serious complications including bronchopulmonary dysplasia, and improves survival rate.
Surfactant replacement was established as an effective and safe therapy for immaturity-related surfactant deficiency by the early 1990s. Systematic reviews of randomized, controlled trials confirmed that surfactant administration in preterm infants with established respiratory distress syndrome (RDS) reduces mortality, decreases the incidence of pulmonary air leak (pneumothoraces and pulmonary interstitial emphysema), and lowers the risk of chronic lung disease or death at 28 days of age.
PG was also directly tested as a component of a synthetic surfactant: one small study (Wilkinson 1985) utilized dry powdered DPPC and phosphatidylglycerol (PG) in the context of RDS treatment. The AARC Clinical Practice Guideline on surfactant replacement therapy recommends that natural exogenous surfactant preparations are recommended over laboratory-derived synthetic suspensions.
Evidence strength for SRT overall: Very strong (multiple randomized controlled trials, systematic reviews). The specific contribution of PG within the multicomponent surfactant preparation has not been independently isolated in controlled human trials; evidence for PG as a solo agent in RDS is therefore indirect.
Evidence strength: Primarily in vitro and animal studies; no published completed phase III human clinical trials identified at time of writing.
Two minor constituents of pulmonary surfactant phospholipids, POPG and PI, have anti-inflammatory effects (by antagonizing activation of TLRs), and antiviral actions against multiple respiratory viruses, including RSV, Influenza A viruses, and most recently SARS-CoV-2.
Respiratory Syncytial Virus (RSV): POPG could markedly attenuate inflammatory responses induced by lipopolysaccharide through direct interactions with the Toll-like receptor 4 (TLR4)-interacting proteins CD14 and MD-2. CD14 and TLR4 have been implicated in the host response to RSV. Treatment of bronchial epithelial cells with POPG significantly inhibited interleukin-6 and -8 production, as well as the cytopathic effects induced by RSV. In quantitative plaque assay studies, both PI and POPG markedly reduced RSV plaque numbers in a dose-dependent manner. At concentrations of 200 μg/ml, both PI and POPG reduced viral plaque numbers by a factor >103 and a factor >104, respectively.
Mycoplasma pneumoniae: Mycoplasma pneumoniae is an important agent of human diseases, producing pharyngitis, bronchiolitis, bronchitis, and community-acquired pneumonia. Although M. pneumoniae is a well-established cause of asthma exacerbations, more recent data have suggested that it may also contribute to the pathogenesis of asthma. In human alveolar macrophage studies, M. pneumoniae membranes and lipoproteins induced a 4-fold increase in arachidonic acid (AA) release from RAW264.7 cells and a 2-fold increase in AA release from primary human alveolar macrophages. POPG significantly antagonized this effect.
Influenza A and SARS-CoV-2: The minor pulmonary surfactant lipids, POPG and phosphatidylinositol (PI), modulate inflammatory response and have potent anti-viral effects against multiple respiratory RNA viruses including RSV, Influenza A virus, and Rhinoviruses. A 2025 conference abstract published in the American Journal of Respiratory and Critical Care Medicine reported that after 16 hours of prophylactic treatment with POPG or PI on ALI-differentiated human bronchial and nasal epithelial cells, the cells were challenged with SARS-CoV-2 and harvested 48 hours post-infection. In bronchial epithelia, POPG and PI reduced viral mRNA expression by approximately 75% and 80%, respectively (n=6). Using nasal epithelial cells, the lipids attenuated SARS-CoV-2 mRNA expression by 75% and 80%, respectively (n=6). For variants, mRNA expression of Delta decreased by 80% with POPG and 85% with PI, and of Omicron by 99% with POPG and 94% with PI. POPG was found to bind to the SARS-CoV-2 ECD S1 protein in a dose-dependent manner. These results are preliminary (in vitro / conference abstract) and have not yet been validated in human clinical trials.
The anionic phospholipids phosphatidylserine (PS) and phosphatidylglycerol (PG) are endogenous phospholipids with anti-inflammatory and immunomodulatory activity. Researchers have investigated whether PG-enriched liposomes could serve as both drug carriers and intrinsically anti-inflammatory agents. In pharmacokinetic studies using fluorescence imaging in vivo, PC liposomes (conventionally formulated) were rapidly cleared from the circulation, while PEGylation resulted in prolongation of liposome circulation. In contrast, PS and PG liposomes, both as conventional or PEGylated formulations, were rapidly cleared. Non-PEGylated PS and PG liposomes accumulated almost exclusively in the liver; PEGylated PS and PG liposomes were observed mainly in liver and spleen. This finding has implications for designing long-circulating formulations. PEGylation of PS and PG liposomes was not effective to prolong the circulation time but caused a higher uptake in the spleen.
Evidence strength: Preclinical. Predominantly in vitro and animal pharmacokinetic data. Human clinical pharmacokinetic studies of PG liposomes as stand-alone therapeutic agents remain limited.
Pulmonary surfactant lipids together with pulmonary surfactant proteins facilitate breathing by reducing surface tension of the air-water interface within the lungs, thereby preventing alveolar collapse. Pulmonary surfactant lipids such as phosphatidylglycerol and phosphatidylinositol participate in the pulmonary host defense and modify immune responses. PG is an essential structural and functional component of the alveolar surfactant film and has a well-established role in lung maturation, biophysical stability of the alveolar interface, and innate immune regulation within the airways.
Two minor components of surfactant phospholipids, PG and phosphatidylinositol (PI), have very potent inhibitory innate immune regulatory activities, which are due to blocking the activation of multiple Toll-like receptors (TLR2/1, TLR3, TLR4, and TLR2/6). This positions PG as a potentially significant endogenous regulator of lung innate immunity.
Via its role as the metabolic precursor to cardiolipin, PG is intimately linked to mitochondrial structure and function. Cardiolipin, synthesized from PG, is required for the assembly and function of the oxidative phosphorylation machinery of the inner mitochondrial membrane.
As described above, PG in amniotic fluid is a well-validated clinical biomarker of fetal lung maturity. Its measurement is used to assess readiness for delivery and the risk of neonatal RDS.
In the context of plant science, PG is essential for normal development. Cardiolipin is a mitochondrial signature phospholipid synthesized from PG and CDP-diacylglycerol. PG biosynthesis is required for embryo development and chloroplast biogenesis, as well as the development of thylakoid membranes and the maintenance of membrane structures in mitochondria.
As a dietary supplement for human consumption, phosphatidylglycerol does not have a formally established or regulatory-reviewed recommended daily intake. The following dosages derive from specific experimental and clinical research contexts:
No established human therapeutic dosing regimen for orally or parenterally administered phosphatidylglycerol as an isolated supplement exists in the peer-reviewed literature reviewed for this article.
Phosphatidylglycerol (PG) is an endogenous phospholipid with anti-inflammatory and immunomodulatory activity, meaning it is a normal constituent of human cell membranes and lung surfactant. Its endogenous status is generally regarded as favorable in terms of baseline biocompatibility.
Pharmacokinetic research reveals a significant safety-relevant pharmacokinetic property: PS and PG liposomes, both as conventional or PEGylated formulations, were rapidly cleared. Non-PEGylated PS and PG liposomes accumulated almost exclusively in the liver. This organ-specific accumulation is relevant to the design and safety assessment of any PG-based therapeutic formulation administered parenterally.
Unlike conventional cationic liposomes, which possess a positive charge that leads to higher, often dose-limiting, cytotoxicity and non-specific binding to blood components, anionic liposomes offer a clear safety advantage. PG-containing anionic liposomes are thus considered less cytotoxic than their cationic counterparts as drug delivery vehicles. The native negative charge minimizes non-specific interaction with negatively charged plasma proteins and cell surfaces.
Research into the anti-inflammatory specificity of POPG shows that its effects are not universal across all PG molecular species. The effect of POPG was specific, insofar as saturated PG, and saturated and unsaturated phosphatidylcholines did not have significant effect on M. pneumoniae-induced AA release. This implies that the acyl chain composition of PG — not merely the glycerol head group — determines its biological activity profile, and that different PG forms may have distinct safety and efficacy characteristics.
Studies testing modified analogs of POPG found that structural changes to the polar headgroup can abolish activity: addition of an amino group at the alkyl-2 position completely abolished the antagonism of TLRs 2 and 4. This underscores the structural specificity of PG's biological effects and implies that manufactured PG preparations must preserve native molecular structure to replicate observed activities.
No comprehensive published toxicological safety dossier specific to orally or parenterally supplemented isolated phosphatidylglycerol in humans was identified in the peer-reviewed literature or government health body databases reviewed for this article. Its safety profile in pharmacological concentrations beyond those encountered as a natural constituent of food lecithins has not been formally characterized in regulatory submissions available to this review.
Within the pharmaceutical industry, phosphatidylglycerol is utilized in the formulation of drug delivery systems. Liposomes, which are spherical vesicles composed of lipid bilayers, often include PG to enhance stability and delivery efficiency. These liposomal formulations are used to encapsulate drugs, improving their bioavailability and targeting specific tissues or cells.
The first closed bilayer phospholipid systems, called liposomes, were described in 1965 and soon were proposed as drug delivery systems. The pioneering work of countless liposome researchers over almost five decades led to the development of important technical advances such as remote drug loading, extrusion for homogeneous size, long-circulating (PEGylated) liposomes, triggered release liposomes, liposomes containing nucleic acid polymers, ligand-targeted liposomes, and liposomes containing combinations of drugs. These advances have led to numerous clinical trials in diverse areas including anti-cancer, anti-fungal, and antibiotic drug delivery, gene medicines, and anesthetics and anti-inflammatory drugs.
PG is a negatively charged structural component used in well-characterized pharmaceutical liposomal products. Phosphatidylserine and phosphatidylglycerol carry a negative net charge at neutral pH 7. The tail groups for each phospholipid can have various lengths (typically C14–C18) and degrees of saturation, allowing formulators to tune biophysical properties of PG-containing preparations for specific therapeutic applications.
Health conditions that Phosphatidylglycerol may help support.
Body systems that Phosphatidylglycerol may help support.
Go back