The Phospholipase A₂ Superfamily in Health and Disease: From Lipid Signaling to Inflammation, Cancer, and Neurodegeneration

Abstract

The phospholipase A₂ (PLA₂) superfamily comprises more than 50 enzymes that differ markedly in structure, catalytic mechanisms, and biological functions. Although all members share the ability to cleave acyl chains from membrane glycerophospholipids, many PLA₂ enzymes catalyze additional reactions that influence membrane composition, lipid signaling, and cellular homeostasis. Through these activities, PLA₂ enzymes contribute to the generation of free fatty acids, lysophospholipids, and downstream lipid mediators and participate in a wide range of physiological processes. Dysregulation of PLA₂ activity has been associated with numerous pathological conditions, including inflammation, cancer, metabolic dysfunction, neurodegeneration, and tissue injury. This review summarizes the major PLA₂ families, outlines their structural and biochemical features, and highlights emerging insights into their roles in health and disease.

INTRODUCTION

Phospholipase A₂ (PLA₂) enzymes were among the earliest lipid-modifying proteins to be described, originating from investigations into the membrane-disrupting properties of snake venoms conducted more than a century ago.¹ These early observations initiated a long trajectory of research demonstrating that PLA₂ enzymes are widely conserved across species and function as central regulators of membrane phospholipid metabolism and lipid mediator signaling.¹,²,³,⁴ Subsequent advances in biochemistry, structural biology, and lipidomics have revealed that PLA₂s constitute a large and heterogeneous superfamily characterized by diverse catalytic strategies and biological activities.⁵,⁶,⁷,⁸,⁹

Although all PLA₂ enzymes share the capacity to cleave an acyl chain from glycerophospholipids (Fig. 1), mammalian PLA₂s vary substantially in domain organization, substrate specificity, Ca²⁺ dependence, and subcellular localization. Based on these biochemical and structural features, PLA₂s are classified into several major families: secreted phospholipase A₂s (sPLA₂s), cytosolic Ca²⁺-dependent phospholipase A₂s (cPLA₂s), Ca²⁺-independent patatin-like phospholipases (Ca²⁺-independent phospholipase A₂ [iPLA₂]/patatin-like phospholipase domain-containing protein [PNPLA] family), platelet-activating factor acetylhydrolases (PAFAHs), lysosomal PLA₂s, and phospholipase A/acyltransferases (PLAATs) (Fig. 2).⁵,⁷,⁸,¹⁰ Each family comprises multiple isoforms with distinct physiological roles, ranging from membrane remodeling and organelle homeostasis to immune regulation, host defense, and metabolic control.³,⁵,⁹,¹¹

Fig. 1. Phospholipase-mediated hydrolysis of membrane phospholipids. (A) Schematic illustration showing the mechanisms through which different phospholipase enzymes act on a membrane phospholipid. PLA₁ cleaves the fatty acid at the sn-1 position, while PLA₂ hydrolyzes the sn-2 ester bond, releasing a FFA and a lysophospholipid. In contrast, PLC and PLD cleave phospholipids within the polar headgroup region, generating diacylglycerol and phosphatidic acid, respectively. (B) Representative reaction catalyzed by PLA₂. Hydrolysis of a glycerophospholipid at the sn-2 position occurs in the presence of water (H₂O), resulting in the production of a lysophospholipid and a FFA. This reaction represents a central step in membrane remodeling and lipid-mediator generation.

PLA₁, phospholipase A₁; PLA₂, phospholipase A₂; FFA, free fatty acid; PLC, phospholipase C; PLD, phospholipase D.

Fig. 2. Classification of major mammalian PLA₂ enzyme families. Overview of the major PLA₂ families in mammals, including sPLA₂, cPLA₂, Ca²⁺-independent patatin-like phospholipases (iPLA₂/PNPLA), PAFAHs, lysosomal PLA₂s, and PLAAT enzymes. Each family is characterized by distinct catalytic mechanisms.

PLA₂, phospholipase A₂; sPLA₂, secreted phospholipase A₂; cPLA₂, cytosolic Ca²⁺-dependent phospholipase A₂; iPLA₂, Ca²⁺-independent phospholipase A₂; PNPLA, patatin-like phospholipase domain-containing protein; PAFAH, platelet-activating factor acetylhydrolase; PLAAT, phospholipase A/acyltransferase; ABHD, α/β-hydrolase domain-containing protein; PLA₁, phospholipase A₁.

PLA₂-mediated hydrolysis liberates free fatty acids and lysophospholipids that function as potent signaling molecules or metabolic precursors. Polyunsaturated fatty acids, including arachidonic acid (AA), eicosapentaenoic acid, and docosahexaenoic acid (DHA), released from membrane phospholipids are subsequently converted into eicosanoids and specialized pro-resolving mediators through cyclooxygenase (COX), lipoxygenase (LOX), or cytochrome P450 pathways.¹¹,¹²,¹³ In parallel, PLA₂-generated lysophospholipids modulate membrane curvature, vesicular trafficking, receptor activity, and inflammatory signaling.⁹,¹⁴ Beyond their classical hydrolytic activity, several PLA₂ family members also exhibit lysophospholipase, transacylase, neutral lipid lipase, or acyltransferase functions, further expanding the mechanistic diversity of this enzyme superfamily.⁸,¹⁰,¹⁴

Genomic and clinical studies have linked dysregulation of specific PLA₂ isoforms to a broad spectrum of human diseases, including cancer, atherosclerosis, neurodegenerative disorders, metabolic dysfunction, and acute or chronic inflammatory conditions.²,³,⁶,¹²,¹⁵ Accordingly, multiple PLA₂ family members are being explored as potential disease biomarkers and therapeutic targets, underscoring their central importance in human physiology and pathology.³,⁷,¹⁵

This review describes the major PLA₂ enzyme families and examines their structural features, catalytic properties, and physiological roles. By integrating findings across multiple PLA₂ subclasses, we highlight how PLA₂-driven lipid metabolism shapes cellular function and contributes to diverse pathological processes.

sPLA₂ FAMILY

sPLA₂ represent the earliest PLA₂ enzymes to be described, with their discovery tracing back to late 19th-century analyses of cobra venom.¹⁶ These enzymes were subsequently recognized as major effector components of the venoms of snakes, scorpions, and other reptiles. In mammals, the sPLA₂ family has expanded to include twelve distinct isoforms—IB, IIA, IIC, IID, IIE, IIF, III, V, X, XIIA, XIIB, and XIV—each belonging to a group of low–molecular-weight proteins (~13–19 kDa) characterized by a rigid disulfide-bond framework that confers high structural stability (Table 1).¹⁷ A conserved Ca²⁺-binding loop and a His/Asp catalytic dyad define the enzymatic core of these proteins (Fig. 3), enabling efficient cleavage of the sn-2 acyl bond of extracellular phospholipids.¹,⁸,¹⁶

Table 1. Summary of sPLA₂ isoforms.

Isoform	Main tissues	Localization	Substrate tendency	Key pathological roles	Reference
sPLA2-IB (PLA2G1B)	Pancreas	Extracellular	Dietary and biliary PC	Obesity, diabetes, atherosclerosis; colitis susceptibility	34,35
sPLA2-IIA (PLA2G2A)	Immune, vascular, intestine	Extracellular	PE/PG (bacterial membranes)	Sepsis, cardiovascular disease, neuroinflammation, cancer biomarker; host defense	33,36
sPLA2-IID (PLA2G2D)	Immune tissues	Extracellular	PUFA-rich PLs	Immune suppression, obesity resistance, cancer immune modulation	46,47
sPLA2-IIE (PLA2G2E)	Skin, adipose, CNS	Extracellular	Membrane PLs	Hair follicle homeostasis, lipid storage, neural repair	50,51
sPLA2-IIF (PLA2G2F)	Skin	Extracellular	PUFA-rich PLs	Psoriasis, epidermal hyperplasia; malaria defense	17,53
sPLA2-III (PLA2G3)	Immune tissues	Extracellular	PC-rich PLs	Fertility, mast-cell activation, cancer, BBB disruption	55,56,57
sPLA2-V (PLA2G5)	Macrophages	Phagosomes/extracellular	PC, PUFA-rich PLs	Obesity protection, Th2 immunity, β-cell regulation	51,62,64
sPLA2-X (PLA2G10)	Adipose, endocrine tissues	Extracellular	PC, PUFA-rich PLs	Lipid metabolism, insulin secretion, fertility, cancer	65,71
sPLA2-XIIA (PLA2G12A)	Broad	Extracellular	Minimal catalytic activity	Antibacterial defense; cancer prognosis	72,73
sPLA2-XIIB (PLA2G12B)	Liver	Secretory pathway	No enzyme activity	VLDL assembly; NAFLD protection	74

sPLA₂, secreted phospholipase A₂; PLA2G, phospholipase A₂ group gene; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PUFA, polyunsaturated fatty acid; PL, phospholipid; CNS, central nervous system; BBB, blood–brain barrier; Th2, T helper 2; VLDL, very-low-density lipoprotein; NAFLD, nonalcoholic fatty liver disease.

Fig. 3. Structural features of sPLA₂ isoforms. Domain architecture of mammalian sPLA₂ isoforms, including sPLA₂-IB, -IIA, -IIC, -IID, -IIE, -IIF, -III, -V, -X, -XII, -XIII, and -XIV. Protein lengths (amino acids) are indicated above each isoform. The catalytic histidine (His) and calcium-binding region (green) are conserved across all sPLA₂ enzymes, enabling efficient extracellular phospholipid hydrolysis.

sPLA₂, secreted phospholipase A₂.

During catalysis, sPLA₂ enzymes coordinate a Ca²⁺-associated water molecule, which is activated by the His/Asp dyad to nucleophilically attack the sn-2 carbonyl group of the phospholipid substrate. Simultaneously, Ca²⁺ stabilizes the reaction intermediate through interactions with the phosphate and carbonyl moieties of the substrate.¹ Because sPLA₂s function in the extracellular milieu, their enzymatic activity is strictly dependent on the presence of extracellular Ca²⁺.¹⁸

Despite their conserved catalytic machinery, sPLA₂ isoforms exhibit pronounced variability in substrate preference. Group III, V, and X enzymes efficiently hydrolyze phosphatidylcholine (PC), whereas group II enzymes preferentially target phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylglycerol (PG).¹⁹ This substrate selectivity underlies the potent bactericidal activity of sPLA₂-IIA against PE- and PG-rich bacterial membranes.²⁰,²¹ Variability is also observed in sn-2 fatty acid selectivity: some isoforms display broad activity, whereas others, including sPLA₂-V, IID, IIF, III, and X, preferentially release polyunsaturated fatty acids such as AA and DHA.¹⁰

1. Physiological functions of sPLA₂ isoforms

Each sPLA₂ isoform exerts distinct biological effects through its ability to liberate bioactive lipids, remodel membrane phospholipids, degrade exogenous lipid substrates, or modify extracellular lipid structures such as lipoproteins and pulmonary surfactants (Table 1).⁹,¹⁰ In addition, sPLA₂s can hydrolyze phospholipids contained within extracellular vesicles or damaged mitochondria, thereby releasing fatty acids with signaling or immunomodulatory potential.²²,²³,²⁴ Many sPLA₂ family members display direct antibacterial activity, particularly against gram-positive bacteria, with a reported potency ranking of group IIA > X > V > XII > IIE > IB/IIF.²⁵,²⁶ For example, group V sPLA₂ is enriched within macrophage phagosomes, implicating this isoform in microbial clearance.²⁷

The expression of multiple sPLA₂ isoforms increases markedly during inflammatory conditions, including rheumatoid arthritis, sepsis, COVID-19, cardiovascular disease, and neurodegenerative disorders.²⁸,²⁹ In septic states, circulating sPLA₂-IIA levels can rise by several thousand-fold.²¹,³⁰ Proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, as well as innate immune receptors such as Toll-like receptors and NOD-like receptors, induce sPLA₂-IIA expression—primarily through nuclear factor κB signaling—across a broad range of cell types, including endothelial, hepatic, renal, muscular, platelet, macrophage, and glial cells.²¹ For this reason, sPLA₂-IIA has been widely investigated as both a disease biomarker and a potential therapeutic target.

Beyond their roles in host defense and inflammation, sPLA₂ enzymes contribute to pulmonary surfactant remodeling, promote the generation of proinflammatory eicosanoids (e.g., prostaglandins, thromboxanes, and leukotrienes), modify low-density lipoproteins into more atherogenic forms, and stimulate the production of cytokines and second messengers, including IL-1, IL-6, TNF-α, and cAMP.³¹,³² These combined activities highlight their central roles in shaping inflammatory and metabolic responses.

sPLA₂ enzymes link extracellular phospholipid metabolism to disease by generating distinct bioactive lipid mediators in an isoform- and tissue-specific manner.³² Through hydrolysis of membrane phospholipids, sPLA₂s release lysophospholipids—particularly lysophosphatidylcholine—and free fatty acids, including AA and DHA. AA serves as a precursor for proinflammatory eicosanoids, such as prostaglandins, thromboxanes, and leukotrienes, which drive inflammation, bronchoconstriction, and immune activation in conditions including arthritis and asthma.³² In contrast, DHA is metabolized into specialized pro-resolving mediators, including resolvins, which suppress excessive immune responses and facilitate the resolution of inflammation. In metabolic tissues, sPLA₂-mediated release of oleic and linoleic acids modulates lipoprotein remodeling and macrophage polarization, thereby influencing obesity and insulin sensitivity.³²,³³ Together, these pathways position sPLA₂s as extracellular lipid editors that translate local phospholipid composition into disease-relevant lipid mediator signaling.

sPLA₂-IB (PLA2G1B)

Loss of sPLA₂-IB protects rodents from diet-induced obesity, diabetes, and atherosclerosis, indicating an important role for this enzyme in lipid absorption and metabolic homeostasis.³⁴ Mice deficient in sPLA₂-IB also exhibit resistance to dextran sulfate sodium–induced colitis, an effect associated with enhanced preservation of intestinal stem cells and reduced inflammatory infiltration.³⁵

sPLA₂-IIA (PLA2G2A)

sPLA₂-IIA serves as an important biomarker for multiple human diseases, including cardiovascular disorders, sepsis, cholangiocarcinoma, and chronic allograft failure.³⁶,³⁷ Functionally, this isoform drives AA release and reactive oxygen species (ROS) generation through COX- and LOX-dependent pathways,³⁶ participates in innate host defense,³³ and promotes Th2 immunity via B1a-cell activation.³⁸ In addition, sPLA₂-IIA contributes to pulmonary fibrosis and atherosclerosis,³⁹ enhances glucose utilization through UCP1 induction in brown fat,⁴⁰ modulates placental ischemia,⁴¹ suppresses gastrointestinal tumorigenesis but supports pancreatic ductal adenocarcinoma survival,⁴² shapes gut microbiota with systemic immunological consequences,⁴³ and participates in ocular surface inflammation. Notably, inhibition of sPLA₂-IIA has been shown to attenuate neuroinflammation-associated neurodegeneration. In the context of progranulin deficiency, elevated sPLA₂-IIA activity enhances membrane phospholipid hydrolysis, resulting in increased circulating prostaglandins—predominantly PGE₂ and PGD₂—and unsaturated free fatty acids. This lipid excess amplifies inflammation, gliosis, and lysosomal dysfunction. Pharmacological inhibition of sPLA₂ using LY333013, a broad sPLA₂ inhibitor, or KH064, a more selective sPLA₂-IIA inhibitor, suppresses phospholipid hydrolysis, normalizes lipid mediator levels, and markedly rescues neuroinflammatory and lysosomal phenotypes.⁴⁴ These findings demonstrate that targeting lipid-releasing enzymes can rebalance inflammatory lipid signaling and restore cellular homeostasis in progranulin-associated neurodegeneration.⁴⁵

sPLA₂-IID (PLA2G2D)

sPLA₂-IID exerts anti-inflammatory and metabolic effects, reducing obesity, insulin resistance, and chronic inflammation⁴⁶ In cancer, this isoform enhances angiogenesis and glycolytic reprogramming in non-small cell lung cancer (NSCLC)⁴⁷ and correlates with immune infiltration and prognosis in cervical carcinoma.⁴⁸ sPLA₂-IID also promotes skin tumor growth by suppressing anti-tumor T helper 1 immune responses.⁴⁹

sPLA₂-IIE (PLA2G2E)

sPLA₂-IIE regulates hair-follicle homeostasis,⁵⁰ modulates lipoprotein lipid composition, and influences adipose and hepatic lipid storage via ERK/HSL signaling.⁵¹ In the central nervous system (CNS), sPLA₂-IIE-derived 15-HETrE supports neural repair after ischemic injury.⁵²

sPLA₂-IIF (PLA2G2F)

This isoform contributes to epidermal hyperplasia and psoriatic pathology,¹⁷,⁵³ while simultaneously conferring host protection against Plasmodium infection.⁵⁴

sPLA₂-III (PLA2G3)

sPLA₂-III plays an essential role in male fertility by supporting epididymal sperm maturation.⁵⁵ It also functions as a mast-cell activator that contributes to anaphylaxis and atherosclerosis,⁵⁶ and its dysregulation has been linked to colon, ovarian, and lung cancer.⁵⁷,⁵⁸ In addition, sPLA₂-III protects against asthma by reducing airway hyperresponsiveness⁵⁹ and promotes blood–brain barrier disruption during meningitis.⁶⁰

sPLA₂-V (PLA2G5)

sPLA₂-V protects against metabolic dysfunction by limiting obesity and insulin resistance⁵¹ and has been associated with benign flecked retina.⁶¹ This isoform enhances Th2 immune responses,⁶² promotes macrophage phagocytosis via LPE generation,⁶³ and regulates β-cell proliferation and insulin secretion.⁶⁴

sPLA₂-X (PLA2G10)

This isoform reduces adipose lipid accumulation,⁶⁵ promotes cancer-cell proliferation in soft-tissue leiomyosarcoma,⁶⁶,⁶⁷,⁶⁸ contributes to fertility,⁶⁹ influences adrenal steroidogenesis,⁷⁰ and regulates insulin secretion through COX-2–dependent pathways.⁷¹

sPLA₂-XIIA (PLA2G12A)

sPLA₂-XIIA exhibits antibacterial activity against Helicobacter pylori and other gram-negative pathogens.⁷² Loss of this enzyme increases cancer-cell invasiveness and correlates with prognosis in early-stage colorectal carcinoma.⁷³

sPLA₂-XIIB (PLA2G12B)

sPLA₂-XIIB plays a central role in hepatic very-low-density lipoprotein assembly and secretion, protecting against hepatic steatosis.⁷⁴,⁷⁵,⁷⁶ In addition, this isoform has emerged as a diagnostic and prognostic biomarker for cholangiocarcinoma.³⁷

cPLA₂ FAMILY

The cPLA₂ family consists of 6 isoforms—cPLA₂α, cPLA₂β, cPLA₂γ, cPLA₂δ, cPLA₂ε, and cPLA₂ζ—which are widely expressed in multiple organs, including the liver, pancreas, brain, testis, and heart (Table 2).⁷⁷ The first isoform to be identified, cPLA₂α, was discovered in human platelets and neutrophils in 1986.¹⁶ Each cPLA₂ family member contains 2 major functional domains connected by a flexible linker region: an N-terminal Ca²⁺-dependent lipid-binding C2 domain and a C-terminal catalytic “lipase” domain that mediates enzymatic activity (Fig. 4).⁷⁸

Table 2. Summary of cPLA₂ isoforms.

Isoform	Main tissues	Localization	Substrate tendency	Key pathological roles	Reference
cPLA2α (PLA2G4A)	Ubiquitous	Cytosol → ER/Golgi	AA-containing PLs	Central inflammatory driver, AD, cancer, colitis, platelet activation	85,95,99
cPLA2β (PLA2G4B)	Ubiquitous	Cytosol	Broad PLs	Immunometabolic regulation	104
cPLA2γ (PLA2G4C)	Heart, brain, skeletal muscle	Membranes	PL remodeling	Lipid droplets, viral replication	106,107
cPLA2δ (PLA2G4D)	Skin (psoriatic lesions)	Cytosol	PLA1 > PLA2	Epidermal barrier dysfunction, psoriasis	111
cPLA2ε (PLA2G4E)	Heart, brain, skeletal muscle, skin	Cytosol	NAPE/NAE pathway	Anti-inflammatory lipids, ischemia protection, cognition	90,116
cPLA2ζ (PLA2G4F)	Thyroid, stomach, large intestine	Mitochondria	AA release	Cardio-protection	91

cPLA₂, cytosolic phospholipase A₂; PLA2G, phospholipase A₂ group gene; ER, endoplasmic reticulum; AA, arachidonic acid; PL, phospholipid; AD, Alzheimer’s disease; PLA₁, phospholipase A₁; PLA₂, phospholipase A₂; NAPE, N-acylphosphatidylethanolamine; NAE, N-acylethanolamine.

Fig. 4. Domain architecture of cPLA₂ isoforms. Schematic representation of cPLA₂ family members (cPLA₂α, β, γ, δ, ε, and ζ) with protein lengths (amino acids) indicated. The C2 domain (black) mediates Ca²⁺-dependent membrane association, the lipase catalytic domain (yellow) contains the active Ser and Asp, which together form the catalytic dyad. PBDs (blue) contribute to membrane targeting and regulatory interactions. cPLA₂β also contains a JmjC domain (green) and cPLA₂γ lacks the C2 domain.

cPLA₂, cytosolic Ca²⁺-dependent phospholipase A₂; Ser, serine; Asp, aspartic acid; PBD, polybasic domain.

cPLA₂ enzymes are activated by elevations in intracellular Ca²⁺, which promote C2-domain–mediated membrane association and substrate engagement.⁷⁸ The catalytic domain contains a conserved Ser/Asp dyad that is essential for phospholipid hydrolysis (Fig. 4).¹⁰ Full enzymatic activity requires the coordinated function of both domains. In addition to their canonical PLA₂ activity, cPLA₂ isoforms also exhibit lysophospholipase and transacylase activities.⁷⁹,⁸⁰,⁸¹ These enzymes display strong selectivity for arachidonate-containing phospholipids, hydrolyzing substrates in the following order: PC > phosphatidylinositol > PE > phosphatidic acid > PS.⁸ When PC serves as the substrate, the preference for sn-2 fatty acids follows the following hierarchy: arachidonic (20:4) > linolenic (18:3) > linoleic (18:2) > oleic (18:1) > palmitoleic (16:1).⁸,⁸⁰

1. Physiological functions

cPLA₂α (group IVA PLA₂) is the most extensively studied member of the cPLA₂ family and exhibits a strong preference for arachidonate-containing phospholipids. Through its capacity to liberate AA, cPLA₂α contributes to the generation of bioactive lipid metabolites involved in inflammation, cancer progression, and neurological disorders.⁶,⁷⁶,⁷⁷ Upon activation, cPLA₂α translocates from the cytosol to PC-rich membranes of the Golgi apparatus and endoplasmic reticulum. This process is tightly regulated by phosphorylation events mediated by several protein kinases, including mitogen-activated protein kinases.⁷⁷,⁸²,⁸³ In Alzheimer’s disease, amyloid-β activates cPLA₂α, promoting AA release and subsequently accelerating amyloid-β accumulation.⁷⁹,⁸⁴ cPLA₂α also induces tau hyperphosphorylation, leading to cytoskeletal instability and impaired synaptic function. Given its central involvement in Alzheimer’s disease pathogenesis, inhibition of cPLA₂α is considered a promising therapeutic strategy.⁸⁰,⁸⁵

Other cPLA₂ isoforms exhibit distinct enzymatic properties. cPLA₂β (group IVB PLA₂) contains a truncated N-terminal JmjC domain (Jumonji C domain) upstream of the C2 domain and displays PLA₁, PLA₂, and lysophospholipase activities.⁷⁴,⁸⁰ cPLA₂γ (group IVC PLA₂) lacks the canonical C2 domain but retains PLA₂, lysophospholipase, and transacylase activities.⁷⁵,⁸¹ cPLA₂ε catalyzes the Ca²⁺-dependent transfer of an acyl chain from glycerophospholipids to PE, generating N-acylphosphatidylethanolamine (NAPE), which is subsequently converted to N-acylethanolamines (NAEs)—lipid mediators with potent anti-inflammatory effects during tissue ischemia and skin injury.⁸¹,⁸²,⁸³,⁸⁶,⁸⁷,⁸⁸,⁸⁹,⁹⁰ Finally, cPLA₂ζ exhibits both PLA₁ and PLA₂ activities without marked preference for specific fatty acid substrates.⁸⁴,⁹¹ Together, these enzymes participate in a wide range of physiological and pathological processes, underscoring the functional diversity of the cPLA₂ family.

cPLA₂α (PLA2G4A)

cPLA₂α is a central regulator of lipid signaling and influences numerous biological processes across diverse tissues. In inflammatory conditions such as ulcerative colitis, cPLA₂α is required for the generation of proinflammatory lipid mediators that sustain disease activity. Elevated or dysregulated cPLA₂α activity has also been associated with the development and progression of several cancers, including lung, liver, breast, and colon malignancies, in which AA-derived lipid mediators support tumor growth, angiogenesis, and immune evasion.⁹²,⁹³,⁹⁴,⁹⁵ Beyond inflammation and cancer, cPLA₂α plays important physiological roles. Its enzymatic activity supports normal ovulation and fertilization, underscoring its contribution to reproductive function.⁸³,⁹⁶ In the liver, cPLA₂α helps coordinate lipid metabolism with inflammatory signaling, thereby influencing hepatic lipid accumulation and metabolic homeostasis.⁹⁷ In the kidney, cPLA₂α contributes to the regulation of renal blood flow, which is essential for maintaining normal renal function.⁹⁸

cPLA₂α also participates in vascular and immune responses. By promoting platelet aggregation at sites of vascular injury, it supports effective hemostasis and clot formation.⁹⁹ Concurrently, cPLA₂α enhances the recruitment of innate immune cells, including neutrophils and macrophages, to sites of tissue damage, thereby supporting inflammatory responses and tissue repair.¹⁰⁰

Within the CNS, cPLA₂α has been implicated in brain injury, spinal cord injury, and neurodegenerative disorders. One of its key pathogenic mechanisms involves the induction of lysosomal membrane permeabilization, which disrupts neuronal homeostasis and promotes neuronal damage.⁷⁹,¹⁰¹,¹⁰²,¹⁰³ cPLA₂α activity has also been associated with synaptic dysfunction and neuronal alterations observed in chronic depression.¹⁰¹,¹⁰²,¹⁰³ Given its prominent role in neuroinflammation and neurodegeneration, reducing PLA2G4A enzymatic activity is actively being explored as a potential therapeutic strategy for Alzheimer’s disease.⁸⁵

cPLA₂β (PLA2G4B)

cPLA₂β (group IVB PLA₂) contains a distinctive N-terminal JmjC regulatory domain and exhibits phospholipase A₁, phospholipase A₂, and lysophospholipase activities.⁸⁰ Although less extensively studied than cPLA₂α, cPLA₂β has been implicated in immunometabolic regulation. In monocytes, increased cPLA₂β expression reduces cellular energy metabolism, suggesting a role in modulating metabolic–inflammatory interactions.¹⁰⁴ These findings indicate that cPLA₂β may participate in cellular lipid remodeling and inflammatory regulation through mechanisms distinct from those of cPLA₂α.

cPLA₂γ (PLA2G4C)

cPLA₂γ (group IVC PLA₂) lacks the canonical Ca²⁺-dependent C2 domain present in other cPLA₂ family members but retains robust PLA₂, lysophospholipase, and transacylase activities.⁸¹ Functionally, this isoform is involved in nuclear membrane remodeling during oocyte maturation, establishing a role in reproductive biology.¹⁰⁵ cPLA₂γ also induces hepatic lipid droplet accumulation¹⁰⁶ and contributes to viral biology by supporting hepatitis C virus replication and assembly.¹⁰⁷,¹⁰⁸ Importantly, this isoform acts during niacin-mediated phospholipid remodeling and signal transduction, regulating the action of receptors and downstream pathways.¹⁰⁹ Tumor cells can survive under stress by inhibiting apoptosis,¹¹⁰ which may contribute to cancer progression.

cPLA₂δ (PLA2G4D)

cPLA₂δ (group IVD PLA₂) exhibits substantially higher PLA₁ than PLA₂ activity and is markedly upregulated in psoriatic skin lesions. Elevated expression of this isoform contributes to epidermal barrier regulation and keratinocyte homeostasis, suggesting a role in chronic skin inflammation and tissue remodeling.¹¹¹,¹¹² These properties indicate that cPLA₂δ participates in cutaneous immune signaling and may serve as a molecular link between lipid metabolism and skin pathology.

cPLA₂ε (PLA2G4E)

cPLA₂ε (group IVE PLA₂) catalyzes the Ca²⁺-dependent transfer of acyl groups from glycerophospholipids to PE, generating NAPE, a precursor of NAEs.⁸⁷,⁸⁸,⁸⁹,⁹⁰ These NAEs exert potent anti-inflammatory and cytoprotective effects, particularly during tissue ischemia and skin injury. Beyond its enzymatic role in NAE biosynthesis, cPLA₂ε regulates membrane trafficking through clathrin-independent endocytosis¹¹³ and has been implicated in neurological and psychiatric conditions, including panic disorder.¹¹⁴ In inflammatory settings, cPLA₂ε contributes to the production of anti-inflammatory NAEs in psoriatic tissue,¹¹⁵ increases serotonin synthesis in interferon (IFN)-γ–stimulated intestinal epithelial cells,¹¹⁶ and improves learning and memory deficits in Alzheimer’s disease models.¹¹⁷ cPLA₂ε also inhibits GLUT4 translocation in skeletal muscle, thereby reducing insulin-stimulated glucose uptake,¹¹⁸ and appears to play dual roles in ischemia by generating cytoprotective NAEs while also promoting lysosomal membrane permeabilization and necroptosis under severe stress.⁹⁰,¹¹⁹

cPLA₂ζ (PLA2G4F)

cPLA₂ζ exhibits both PLA₁ and PLA₂ activities with minimal specificity for the sn-2 fatty acid. Knockdown of PLA2G4F in fibroblasts decreases oleic acid release, demonstrating its role in fatty acid remodeling. It also mediates Ca²⁺-dependent AA release from mitochondria, where it is converted to epoxyeicosatrienoic acids, conferring cardioprotective effects against heart failure.⁹¹

Ca²⁺-iPLA₂ (PNPLA) FAMILY

The Ca²⁺-₂iPLA₂ enzymes, also known as patatin-like phospholipase domain-containing lipases (PNPLA1–9), share a conserved patatin domain that was first identified in patatin (iPLA₂α) from potato (Table 3).¹⁰ PNPLAs contain a lipase consensus sequence (GXSXG, where X denotes any amino acid) and a putative ATP-binding motif. Their active site resides within the patatin-like (α/β) fold and includes a Ser–Asp catalytic dyad and an oxyanion hole (Fig. 5).¹²⁰ The catalytic serine is located within the GXSXG motif, whereas the aspartate typically occurs within an Asp-Gly-Ala/Gly motif found in many lipases. During catalysis, the nucleophilic hydroxyl group of serine forms a covalent acyl–enzyme intermediate with the substrate, while aspartate acts as a general acid/base to facilitate substrate binding and turnover. The oxyanion hole, positioned near the catalytic dyad, stabilizes the transition state during substrate hydrolysis.¹²⁰ None of the PNPLA enzymes requires Ca²⁺ for catalytic activity.

Table 3. Summary of iPLA₂ (PNPLA family).

Isoform	Main tissues (reported)	Localization	Preferred activity	Key pathological roles	Reference
PNPLA1	Skin	Lipid droplets	Acylceramide synthesis	Epidermal barrier integrity	123
PNPLA2 (ATGL)	Adipose, liver	Lipid droplets	TAG hydrolysis	Core lipolysis, energy metabolism	124
PNPLA3	Liver, adipose	Lipid droplets	TAG/retinyl esters	NAFLD, NASH, fibrosis	130
PNPLA4	Liver, adipose tissue	Lipid droplets	Retinyl ester/phospholipid hydrolysis	Retinoid metabolism	121
PNPLA5	Adipose	Lipid droplets	TAG hydrolysis	Autophagy, lipid balance	131
PNPLA6 (NTE)	Neurons	ER, lipid droplets	Phospholipids	Neurodegeneration, organophosphate toxicity	134
PNPLA7	Muscle, testes	ER, lipid droplets	Lysophospholipase	Energy homeostasis	129
PNPLA8	Brain, muscle	Mitochondria	Cardiolipin	Neurodegeneration	120
PNPLA9 (PLA2G6)	Brain	Cytosol/organelles	Oxidized PLs	AD, Parkinson's disease, ferroptosis control	120

iPLA₂, Ca²⁺-independent phospholipase A₂; PNPLA, patatin-like phospholipase domain-containing protein; ATGL, adipose triglyceride lipase; TAG, triacylglycerol; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NTE, neuropathy target esterase; ER, endoplasmic reticulum; PLs, phospholipids; PLA2G, phospholipase A₂ group gene; AD, Alzheimer’s disease.

Fig. 5. Patatin-like phospholipase (PNPLA/iPLA₂) family structure. Structural organization of PNPLA family members (PNPLA1–9) with protein lengths (amino acids) shown. All PNPLA proteins share a conserved patatin domain (black) harboring a Ser–Asp catalytic dyad. PNPLA6 and PNPLA7 also contain a cyclic nucleotide monophosphate-binding domain (green) and PNPLA9 contains ankyrin repeats domain (blue).

PNPLA, patatin-like phospholipase domain-containing protein; iPLA₂, Ca²⁺-independent phospholipase A₂; Ser, serine; Asp, aspartic acid.

Although classified as PLA₂s, several PNPLAs exert additional activities, including lysophospholipase, transacylase/acyltransferase, neutral lipid lipase, and retinyl-ester hydrolase functions. Generally, PNPLA members with extended N-terminal regions (PNPLA6–9) act primarily on phospholipids as PLA₁/PLA₂ or lysophospholipases, whereas PNPLA1–5 preferentially target neutral lipids as lipases or transacylases.¹⁰,¹²¹ Notably, PNPLA3 and PNPLA4 display retinyl-esterase activity and contribute to retinol metabolism.¹²¹,¹²²

1. Physiological functions

Skin barrier function

PNPLA1 catalyzes the ω-O-esterification step in acylceramide biosynthesis, generating acylceramides that are essential for epidermal barrier integrity and protection against transepidermal water loss and pathogen entry.¹²³ PNPLA1 deficiency disrupts linoleoyl ω-O-esterification of ceramides, resulting in severe barrier defects and aberrant keratinocyte differentiation, thereby underscoring its central role in skin homeostasis.

Metabolic regulation

PNPLA2 and PNPLA3 are highly expressed in adipose tissue and liver. PNPLA2 (also known as ATGL) expression increases during fasting, whereas PNPLA3 expression rises with feeding, indicating opposing roles in lipid handling.¹²⁴ PNPLA2/ATGL functions as the rate-limiting lipase for triacylglycerol (TAG) hydrolysis in adipose tissue, muscle, and liver.¹²⁴ By mobilizing free fatty acids from TAGs, PNPLA2 supports energy metabolism; however, when dysregulated, it has been associated with insulin resistance, nonalcoholic fatty liver disease (NAFLD), and cancer progression. PNPLA3—particularly the I148M variant—alters TAG, retinyl ester, and lysophosphatidic acid metabolism, leading to hepatic lipid accumulation and contributing to the development and progression of NAFLD, nonalcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma.¹²⁵,¹²⁶,¹²⁷

Hepatic phospholipid/choline metabolism

PNPLA7 and PNPLA8 participate in hepatic PC breakdown, producing endogenous glycerophosphocholine and choline.¹²⁸ PNPLA7, also known as neuropathy target esterase–related esterase, functions as a lysophospholipase whose expression increases during fasting and decreases with feeding in mouse skeletal muscle, reflecting regulation by insulin, glucocorticoids, and catecholamines.¹²⁹ Mice lacking PNPLA7 develop hypoglycemia, hypolipidemia, and reduced energy expenditure, demonstrating its importance in systemic energy homeostasis. PNPLA7 also influences hepatic very-low-density lipoprotein secretion through interactions with apolipoprotein E, and perturbations in this pathway may contribute to metabolic dysfunction. PNPLA8 supports mitochondrial integrity by hydrolyzing cardiolipin; altered PNPLA8 activity compromises mitochondrial function in liver and skeletal muscle and increases susceptibility to apoptosis. PNPLA3 similarly contributes to the maintenance of hepatic triglyceride balance by coordinating triglyceride storage and secretion.¹³⁰

Autophagy and lipid signaling

PNPLA5 (GS2-like) exhibits TAG hydrolase activity and is required for optimal initiation of autophagy.¹³¹ PNPLA5 deficiency is associated with elevated serum cholesterol, TAGs, and high-density lipoprotein cholesterol, abnormal bleeding, and reduced male fertility due to testicular apoptosis.¹³² Conversely, PNPLA5 deficiency has also been reported to protect against NAFLD by modulating inflammatory signaling, improving mitochondrial function, and increasing high-density lipoprotein cholesterol levels.¹³³

Neurological functions

PNPLA6 (neuropathy target esterase) is widely expressed in neurons during postnatal development and later becomes enriched in the cerebral cortex, olfactory bulb, pons, thalamus, hypothalamus, and medulla oblongata.¹³⁴,¹³⁵,¹³⁶ PNPLA6 hydrolyzes PC and lysophosphatidylcholine to maintain membrane homeostasis. Inhibition or mutation of PNPLA6 has been linked to organophosphate-induced delayed neuropathy and broader neurodegenerative processes, highlighting its essential role in neuronal development and brain function.¹²⁶,¹³⁷ Mutations in PNPLA6 cause autosomal recessive syndromes, including Boucher–Neuhauser, Gordon–Holmes, Oliver–McFarlane, and Laurence–Moon syndromes, and—together with PNPLA8 deficiency—are associated with neurodegeneration characterized by movement disorders and cognitive impairment.¹²⁰,¹³⁸,¹³⁹

PNPLA9, ferroptosis, and disease

PNPLA9 releases AA, linoleic acid, and lysophospholipids, which are subsequently converted into prostaglandins (e.g., PGE₂ and PGD₂), leukotrienes (e.g., LTB₄ and LTC₄), and hydroxyeicosatetraenoic acids in immune cells. These lipid mediators promote macrophage and T-cell activation, monocyte chemotaxis, ROS generation, and cytokine production, thereby linking PNPLA9 activity to autoimmune diseases—including type 1 diabetes, multiple sclerosis, and rheumatoid arthritis—as well as atherosclerosis, vascular injury, and chronic inflammation. Conversely, PNPLA9 also contributes to the generation of EPA- and DHA-derived specialized pro-resolving mediators, highlighting its dual role in both the initiation and resolution of inflammatory responses.¹⁴⁰

Dysregulation of PNPLA9 has been associated with Alzheimer’s disease, Parkinson’s disease, Karak syndrome, infantile neuroaxonal dystrophy, and other neurological disorders.¹²⁰,¹⁴⁰,¹⁴¹,¹⁴²,¹⁴³ PNPLA9 preferentially hydrolyzes oxidized polyunsaturated fatty acid–containing phospholipids, a property that is particularly relevant to ferroptosis. Functionally, PNPLA9 acts as an anti-ferroptotic regulator, attenuating pro-ferroptotic signaling and influencing cell death, autophagy, and senescence.¹⁴⁴,¹⁴⁵,¹⁴⁶ Because ferroptosis contributes to a wide range of pathologies—including neurological, oncologic, cardiovascular, and renal diseases—PNPLA9 represents a critical node linking lipid remodeling to disease progression. Beyond the nervous system, PNPLA9 also participates in cell growth and migration, autophagy, insulin secretion, bone formation, and vascular contractility and relaxation.¹²⁰,¹⁴⁵,¹⁴⁶,¹⁴⁷

PAFAHs

PAFAHs were initially purified as enzymes capable of hydrolyzing the acetyl group at the sn-2 position of platelet-activating factor (PAF; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a potent phospholipid mediator involved in a wide range of physiological and pathological processes.¹⁴⁸ In mammals, 3 types of PAFAHs have been identified: 1 plasma form and 2 intracellular forms—plasma PAFAH, PAFAH2, and PAFAH1B.¹⁴⁸,¹⁴⁹

PAFAH1B is a multimeric complex composed of 2 catalytic subunits, PAFAH1B2 (α1) and PAFAH1B3 (α2), and a regulatory, non-enzymatic subunit, PAFAH1B1 (β).¹⁰,¹⁵⁰ Unlike many PLA₂ enzymes, PAFAHs do not require Ca²⁺ for catalysis. Members of the PAFAH family share a conserved α/β-hydrolase fold and utilize a Ser–His–Asp catalytic triad, in contrast to the Ser–Asp dyad characteristic of most PLA₂s (Fig. 6).¹⁶

Fig. 6. PAFAH family. Domain organization of plasma and intracellular PAFAH enzymes, including plasma PAFAH (PLA2G7), PAFAH2, and the PAFAH1B complex (PAFAH1B1, PAFAH1B2, and PAFAH1B3). These enzymes possess an α/β-hydrolase fold and utilize a Ser–His–Asp catalytic triad. PAFAH2 also contains a membrane binding domain (black) and plasma PAFAH contains a lipoprotein binding domain (blue). Protein lengths (amino acids) are indicated.

PAFAH, platelet-activating factor acetylhydrolase; PLA2G, phospholipase A₂ group gene; Ser, serine; Asp, aspartic acid; His, histidine.

In human plasma, approximately 70% of plasma PAFAH associates with low-density lipoprotein, with the remaining fraction bound to high-density lipoprotein.¹⁴⁸ Accordingly, plasma PAFAH is also referred to as lipoprotein-associated PLA₂. PAFAHs hydrolyze the acetyl group at the sn-2 position of PAF, generating acetic acid and 1-alkyl-2-lysophosphatidylcholine. Both plasma PAFAH and PAFAH2 preferentially hydrolyze phospholipids containing short sn-2 acyl chains, such as propionyl (C3) and butyryl (C4) groups.

They also act on oxidatively modified phospholipids bearing succinyl, glutaryl, 5-oxovaleroyl, or azelaoyl substituents,¹⁴⁸,¹⁵¹ while exhibiting minimal activity toward phospholipids with 2 long acyl chains. In addition, both enzymes can hydrolyze short-chain diacylglycerols and TAGs and display PLA₁ activity. Plasma PAFAH and PAFAH2 show high affinity for F₂-isoprostane–containing phospholipids, although their catalytic rates are slower than those observed for PAF.¹⁵² Plasma PAFAH also hydrolyzes phospholipid hydroperoxides and exhibits transacetylase activity, whereas PAFAH2 hydrolyzes ω-3 fatty acid epoxides and displays dual hydrolase–transacetylase activity.¹⁵³ In contrast, PAFAH1B selectively hydrolyzes phospholipids containing short acetyl chains.

1. Physiological functions

PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid messenger that functions as a strong chemoattractant and leukocyte activator and participates in key biological processes, including inflammation, anaphylaxis, reproduction, and fetal development.¹⁴⁸,¹⁵¹ Although originally identified in plasma, plasma PAFAH has since been detected in other extracellular fluids, such as milk and urine, particularly under pathological conditions.¹⁵⁴ Dysregulated plasma PAFAH activity has been associated with multiple disease states, and inhibitors targeting this enzyme are currently under evaluation for the treatment of cardiovascular disorders.¹⁴⁸ Accumulating evidence indicates that PAFAH1B1 contributes to tumor initiation and cancer progression.¹⁵⁵,¹⁵⁶,¹⁵⁷ PAFAH2 has recently been identified as an enzyme responsible for generating oxidized ω-3 fatty acids that are required for immunoglobulin E (IgE)–antigen–induced mast-cell activation.¹⁴⁸ In Pafah2^−/− mast cells, levels of these oxidized lipids are markedly diminished; supplementation with ω-3 epoxide species effectively restores the defective phenotypes observed in PAFAH2^−/− cells.¹⁵⁶ The major physiological roles of PAFAH family members are summarized below.

Plasma PAFAH (PLA2G7)

Plasma PAFAH plays an important role in cardiovascular physiology, and its dysregulation has been associated with myocardial infarction, stroke, cardiomyopathy, cerebral hemorrhage, and atherosclerosis.¹⁴⁸ Beyond cardiovascular disease, plasma PAFAH has also been linked to multiple sclerosis, polycystic ovary syndrome, and acute pancreatitis.¹⁴⁸ Notably, plasma PAFAH appears to exert a protective effect in neonatal necrotizing enterocolitis.¹⁵⁷ Elevated plasma PAFAH activity has been associated with colon tumorigenesis,¹⁵⁸ and abnormalities in this enzyme have also been reported in type 1 diabetes, asthma, and several renal disorders.¹⁵⁹

PAFAH2 (PLA2G7B)

PAFAH2 is responsible for generating oxidized ω-3 fatty acids—including 17,18-EpETE and 19,20-EpDPE—that function as key lipid mediators in mast cells following IgE–antigen stimulation.¹⁴⁸ This enzyme also protects cells from oxidative stress-induced apoptosis.¹⁴⁸ In addition, PAFAH2 plays a critical role in suppressing synchronized ferroptosis, thereby mitigating acute kidney injury,¹⁶⁰ and it participates in the regulation of pulmonary vascular remodeling.¹⁶¹ Collectively, these findings highlight PAFAH2 as a multifunctional regulator of lipid signaling and cellular stress responses.

PAFAH1B2 (PAFAH1α1, PLA2G8A)

PAFAH1B2 has been implicated in neurological, metabolic, and reproductive physiology. Deficiency of this subunit reduces amyloid-β production in experimental models of Alzheimer’s disease.¹⁶² Male mice lacking PAFAH1B2 exhibit increased body weight as a consequence of reduced testosterone levels.¹⁶³ Disruption of PAFAH1B2 function also results in infertility, impaired spermatogenesis, and increased apoptosis within seminiferous tubules.¹⁴⁸ In cancer biology, PAFAH1B2 promotes metastasis in pancreatic cancer,¹⁵⁵ whereas its loss suppresses ovarian cancer cell proliferation, migration, and tumorigenicity while promoting apoptosis.¹⁶⁴ These diverse roles underscore the importance of PAFAH1B2 in both tissue homeostasis and disease progression.

PAFAH1B3 (PAFAH1α2, PLA2G8B)

PAFAH1B3 contributes to neuronal development by regulating gene-expression programs required for proper brain function.¹⁶⁵ Downregulation of this subunit suppresses the progression of several cancers through modulation of epithelial–mesenchymal transition pathways.¹⁶⁶,¹⁶⁷,¹⁶⁸,¹⁶⁹ In addition, PAFAH1B3 plays a critical role in oocyte biology, particularly in spindle formation and meiotic progression during bovine oocyte maturation.¹⁷⁰ Together, these findings demonstrate that PAFAH1B3 participates in both developmental processes and cancer regulation.

α/β-HYDROLASE DOMAIN-CONTAINING PROTEINS (ABHDs)

α/β-Hydrolase domain–containing proteins constitute a large and diverse superfamily comprising more than 20 members that share a characteristic α/β-hydrolase fold.¹⁷¹ Their catalytic machinery typically consists of a nucleophile (Ser, Asp, or Cys), a His residue, and an acidic residue (Asp or Glu), together with 2 to 3 residues that form an oxyanion hole.¹⁷¹,¹⁷² Most ABHD proteins contain a GXSXG lipase motif and a conserved His–XXXX–Asp sequence associated with acyltransferase activity (Fig. 7).¹⁷³,¹⁷⁴ Consequently, ABHD family members encompass enzymes with a wide range of catalytic activities—including lipase, acyltransferase, amidase, esterase, protease, thioesterase, and epoxide hydrolase functions—making them one of the most functionally versatile protein families.¹⁷¹,¹⁷²

Fig. 7. ABHD phospholipases. Schematic depiction of ABHD family members involved in lipid metabolism. ABHD enzymes share an α/β-hydrolase fold and contain conserved catalytic residues. The red marks represent the predicted active site lipase domain, while the green marks represent the predicted acyltransferase motif. Protein lengths (amino acids) are indicated.

ABHD, α/β-hydrolase domain-containing protein.

ABHD4 functions as a lipase that hydrolyzes NAPE and lyso-NAPE to generate glycerophospho– NAE, thereby regulating N-acylphospholipid metabolism in the nervous system.⁸¹,¹⁷⁵

1. Physiological functions

Mammalian ABHD proteins participate in a wide range of biological processes, including lipid metabolism, intracellular signaling, metabolic regulation, inflammation, and carcinogenesis.¹⁶⁵,¹⁷⁶ Among these proteins, ABHD6 is one of the most extensively studied members and has been implicated in inflammation, tumorigenesis, adipogenesis, cold-induced thermogenesis, and insulin secretion in pancreatic islets.¹⁶⁶,¹⁶⁷,¹⁶⁸,¹⁶⁹,¹⁷⁰,¹⁷¹,¹⁷⁷,¹⁷⁸,¹⁷⁹,¹⁸⁰,¹⁸¹,¹⁸² Together with monoacylglycerol lipase and ABHD12, ABHD6 contributes to the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG), which is converted into AA and glycerol in the CNS.¹⁷²,¹⁸³ Because 2-AG signaling regulates immune responses, appetite, and pain perception, ABHD6-mediated regulation of monoacylglycerol hydrolysis plays essential roles in pancreatic β cells, macrophages, neurons, and white adipocytes.¹⁷³,¹⁸⁴

Cancer development is closely linked to inflammation, angiogenesis, and dysregulated cell proliferation, processes in which aberrant endocannabinoid signaling involving ABHD6 and ABHD12 may contribute.¹⁷³,¹⁸⁴ ABHD6 is overexpressed in several highly lethal human cancers, including prostate, colorectal, lung, breast, and pancreatic tumors, and pharmacological inhibition of ABHD6 suppresses NSCLC progression. ABHD6 also exhibits bis(monoacylglycero)phosphate (BMP) hydrolase activity in the liver; consequently, ABHD6 inhibition increases hepatic BMP levels and disrupts lysosomal lipid sorting within late endosomes and lysosomes.¹⁷⁴,¹⁷⁵,¹⁷⁶,¹⁸⁵,¹⁸⁶,¹⁸⁷

ABHD11 is essential for cell survival and embryonic stem cell (ESC) development. Loss of ABHD11 induces cell death and disrupts ESC proliferation and differentiation, whereas ABHD11 overexpression prevents apoptosis. These effects are mediated, at least in part, through alterations in GSK3β/β-catenin and extracellular signal-regulated kinase signaling pathways.¹⁷⁷,¹⁸⁸ ABHD5 has also been implicated in autophagy regulation and colorectal cancer development.¹⁷⁸,¹⁸⁹ ABHD2 is frequently overexpressed in breast, ovarian, and prostate cancers, where it enhances cell proliferation and migration through modulation of Akt, p70S6K, and JNK signaling pathways. Elevated ABHD2 expression also increases free fatty acid production and activates β-oxidation in hepatocellular carcinoma, thereby promoting cell proliferation and resistance to apoptosis.¹⁷⁹,¹⁸⁰,¹⁹⁰,¹⁹¹ In contrast, ABHD2 exerts protective effects in asthma and chronic obstructive pulmonary disease by inhibiting PI3K/Akt signaling, reducing airway smooth muscle migration, and preventing pulmonary emphysema.¹⁸¹,¹⁸²,¹⁹²,¹⁹³ ABHD2 is additionally required for macrophage infiltration into atherosclerotic lesions¹⁸³,¹⁹⁴ and regulates endoplasmic reticulum calcium release.¹⁸⁴,¹⁹⁵

ABHD1 may suppress ROS generation by inhibiting NADPH oxidase activity.¹⁶⁰,¹⁷¹,¹⁸⁵,¹⁹⁶ In addition, ABHD6, ABHD16A, and ABHD17A/B/C function as S-depalmitoylases for N-Ras.¹⁸⁶,¹⁸⁷,¹⁹⁷,¹⁹⁸ Protein palmitoylation—the covalent attachment of fatty acids such as palmitate to cysteine (and, less commonly, serine or threonine) residues—is essential for proper protein trafficking and signal transduction. Depalmitoylation of N-Ras by ABHD proteins may attenuate aberrant Ras signaling and thereby counteract tumor development.¹⁸⁸,¹⁹⁹

ABHD16A also regulates antiviral immunity by modulating the palmitoylation–depalmitoylation cycle of interferon-induced transmembrane (IFITM) proteins. This activity is conserved across human, porcine, and murine IFITM proteins and is required for their correct intracellular localization and antiviral function.¹⁸⁹,²⁰⁰

ABHD5 (also known as CGI-58), although lacking intrinsic hydrolase activity, serves as a key co-activator of ATGL/PNPLA2, the rate-limiting enzyme of triglyceride hydrolysis.¹⁹⁰,¹⁹¹,²⁰¹,²⁰²,²⁰³ Loss-of-function mutations in ABHD5 cause Chanarin–Dorfman syndrome, which is characterized by the accumulation of neutral lipids in multiple organs.

In the reproductive system, ABHD2 is abundantly expressed in the ovary and plays critical roles in follicular development and regulation of the female estrous cycle.¹⁹²,²⁰⁴ ABHD2 deficiency disrupts normal cyclicity, prolongs the estrous phase, shortens the luteal phase, and produces polycystic ovarian morphology; these abnormalities can be partially reversed by gonadotropin treatment. ABHD2 also interacts with progesterone and contributes to sperm chemotaxis and the acrosome reaction.¹⁹³,²⁰⁵

Several ABHD proteins are essential for neurological function. Mutations in ABHD12 cause PHARC syndrome, a rare neurodegenerative disorder characterized by cataracts, retinitis pigmentosa, polyneuropathy, hearing loss, and ataxia.¹⁹⁴,²⁰⁶ ABHD12 metabolizes phytanic acid, and its loss results in toxic accumulation of phytanic acid and related lipids, leading to progressive neurodegeneration.¹⁹⁵,²⁰⁷ Inhibition of endocannabinoid hydrolases—particularly ABHD12—has been proposed as a strategy to reduce neuroinflammation and ameliorate symptoms in multiple sclerosis and related neurological disorders.¹⁹⁴,¹⁹⁶,²⁰⁶,²⁰⁸ ABHD12 preferentially degrades lysophosphatidylserine, thereby maintaining membrane lipid homeostasis and normal microglial and neuronal function; dysfunction of this pathway results in neurodegeneration.²⁰⁰

LYSOSOMAL PLA₂s

1. PLA2G15

PLA2G15 is ubiquitously expressed and localized to lysosomes and late endosomes. This enzyme exhibits optimal activity at acidic pH, is Ca²⁺ independent, and functions as both an acyltransferase and an acidic phospholipase.²⁰⁹ PLA2G15 contains a signal peptide and a consensus serine hydrolase lipase motif (AXSXG), in which serine, aspartate, and histidine form the catalytic triad.²⁰⁹ PLA2G15 hydrolyzes both sn-1 and sn-2 acyl chains and thereby contributes to lysosomal phospholipid catabolism. Documented substrates include PC, PE, PG, and PS, with minimal activity toward phosphatidylinositol or sphingomyelin.²⁰⁹,²¹⁰ In addition, PLA2G15 can serve as a 1-O-acyl-ceramide synthase to produce acylceramide.²¹¹

Functionally, PLA2G15 is required for autophagic cargo processing within lysosomes²¹² and is essential for generating the lysosome-specific lipid BMP by producing lysophosphatidylglycerol, a BMP precursor.¹⁸⁷,²¹⁰ Intriguingly, recent studies suggest that PLA2G15 also functions as a BMP hydrolase, as genetic ablation or pharmacological inhibition of PLA2G15 results in elevated BMP levels.²¹⁰,²¹³,²¹⁴ Increased BMP enhances lysosomal lipid degradation and promotes cholesterol efflux, a mechanism that is particularly relevant in lysosomal storage disorders, where modulation of the PLA2G15–BMP axis improves lysosomal function and alleviates neurodegenerative pathology. Together, PLA2G15 and BMP form a regulatory lipid–enzyme pair that fine-tunes lysosomal metabolism and cellular homeostasis. Although the precise role of PLA2G15 in BMP turnover remains incompletely defined, deletion of PLA2G15 induces lysosomal phospholipidosis in alveolar macrophages, characterized by surfactant phospholipid accumulation, reduced presentation of lysophospholipid antigens to CD1d on invariant natural killer T cells, and impaired adaptive T-cell immunity to Mycobacterium.²¹⁴ Moreover, inhibition of PLA2G15—secondary to glycerophosphodiester accumulation in CLN3 deficiency—has been implicated in Batten disease (juvenile neuronal ceroid lipofuscinosis).²¹⁵,²¹⁶ PLA2G15-deficient mice also show defective IFN-γ release and increased apoptotic sensitivity to oxidized low-density lipoprotein,²¹⁴ and PLA2G15 appears atheroprotective in murine models.²¹⁷

2. Peroxiredoxin 6 (Prdx6)

Prdx6, also known as acidic Ca²⁺-independent ₂PLA₂, is localized to the cytosol, lysosomes and lysosome-related organelles, and the extracellular space.²¹⁸ Its PLA₂ activity is modest at cytosolic pH but increases substantially following phosphorylation, under acidic conditions, or in the presence of oxidized phospholipid substrates. Although the precise lysosomal functions of Prdx6 remain to be fully elucidated, its context-dependent activation suggests a role in redox-lipid crosstalk within acidic intracellular compartments.

PLAAT (HRASLS) FAMILY

The PLAAT (also known as HRASLS) family was initially identified as a group of tumor suppressors that antagonize RAS signaling; all members exhibit Ca²⁺-independent enzymatic activity.⁹ The family includes PLAAT1 (HRASLS1, A-C1), PLAAT2 (HRASLS2, FLJ20556), PLAAT3 (PLA2G16, AdPLA, HREV107), PLAAT4 (RARRES3, TIG3, HRASLS4, RIG1), and PLAAT5 (HRASLS5, HRLP5, iNAT).¹⁰ Although all 5 members are present in humans, only PLAAT1, PLAAT3, and PLAAT5 are expressed in rodents. PLAATs and lecithin retinol acyltransferase share a cysteine-centered catalytic triad, in which cysteine serves as the nucleophile within a conserved NC domain that interacts with 2 histidine residues—except in PLAAT1, where 1 histidine is replaced by asparagine (Fig. 8).⁹,²¹⁹ All family members except PLAAT5 contain a C-terminal hydrophobic segment that is important for subcellular localization.

Fig. 8. PLAAT (HRASLS) family. Schematic representation of PLAAT family members highlighting their conserved domain architecture. PLAAT proteins consist of 3 major regions: an N-terminal PRD (green), a central catalytic domain containing the H-box (red) and NC motif (black), and a C-terminal HD (blue) that mediates membrane association. PLAAT5 lacks the hydrophobic domain, distinguishing it from other family members. Protein lengths (amino acids) are indicated.

PLAAT, phospholipase A/acyltransferase; PRD, proline-rich domain; H-box, histidine box; NC, N-terminal conserved domain; HD, hydrophobic domain; Cys, cysteine; His, histidine.

PLAAT enzymes display several Ca²⁺-independent phospholipid-metabolizing activities, notably NAPE-forming N-acyltransferase (NAT), PLA₁/PLA₂, and O-acyltransferase activities.⁹,²²⁰,²²¹ They cleave sn-1 or sn-2 ester bonds of phospholipids (predominantly PC) and generally prefer sn-1 over sn-2, except PLAAT5, which shows no positional preference.²²²,²²³,²²⁴ By synthesizing NAPE, PLAATs provide precursors for anti-inflammatory NAEs.⁹,²²⁰ In vitro, PLAAT1/2/5 exhibit strong NAT activity. PLAAT1 also shows high O-acyltransferase activity,²²⁰,²²⁵,²²⁶,²²⁷,²²⁸ whereas PLAAT3 exhibits higher PLA₁/PLA₂ activity.²²⁰,²²⁵,²²⁶,²²⁷ Overexpression of any PLAAT elevates NAPE/NAE in cells, indicating that all family members can function as NATs in vivo.⁹,²²⁰ For instance, PLAAT5 markedly increases anandamide and other polyunsaturated NAEs in U2OS cells.²²⁹ Collectively, Ca²⁺-independent PLAATs help maintain basal NAPE pools across tissues.²²⁰,²²⁹,²³⁰

1. Physiological roles

Among PLAAT family members, only PLAAT1, PLAAT3, and PLAAT5 are expressed in rodents, with PLAAT1 and PLAAT3 being the most extensively studied. PLAAT1 is highly expressed in skeletal muscle, brain, heart, and testis in both humans and rodents, whereas PLAAT3 is ubiquitously expressed but enriched in adipocytes, where it contributes to antilipolytic activity in adipose tissue.²³¹,²³² In HEK293 cells, PLAAT1 overexpression increases cardiolipin content through PC:MLCL transacylase activity and localizes to the outer mitochondrial membrane.²³³ Excessive PLAAT1 expression remodels mitochondrial phospholipids, leading to mitochondrial fragmentation and loss of peroxisomes in cultured cells; however, the physiological relevance of these mitochondrial alterations in vivo—particularly in muscle and heart—remains unclear.²³⁴ Interestingly, PLAAT1-deficient mice exhibit reduced fat accumulation in the liver and skeletal muscle through mechanisms that appear to be independent of its mitochondrial functions.²³⁵

PLAAT enzymes also participate in developmental organelle remodeling. PLAAT1 is required for lens organelle degradation in zebrafish, whereas PLAAT3 mediates this process in mice, consistent with species-specific differences in PLAAT1 expression in the lens.²³⁶ Overexpression studies demonstrate that PLAAT3 induces peroxisome loss through its intrinsic phospholipase activity in HEK293 cells, and that the protein translocates to lysosomes during lysosomal membrane permeabilization.²³⁴,²³⁶,²³⁷,²³⁸,²³⁹ Together, these findings highlight a conserved role for PLAAT enzymes in regulating the structure and turnover of mitochondria, peroxisomes, and lysosomes.²³⁴,²³⁶,²³⁹,²⁴⁰ Beyond organelle biology, PLAAT3 modulates RAS signaling via its PLA/acyltransferase activity by reducing the pool of palmitoylated H-RAS, thereby decreasing levels of active GTP-bound H-RAS and attenuating downstream signaling pathways.²⁴¹,²⁴²

PLAAT1 (HRASLS1, A-C1)

PLAAT1 plays a critical role in developmental organelle clearance. In zebrafish, PLAAT1 is required for lens organelle degradation, underscoring its involvement in tissue remodeling during development.²³⁶ The marked mitochondrial morphological alterations and peroxisomal depletion induced by PLAAT1 overexpression in HEK293 cells are consistent with its potent phospholipase-mediated remodeling capacity.²³⁴ Upregulation of PLAAT1 also promotes viral replication in cultured cells, suggesting a potential role in host–virus interactions.²⁴³ In vivo, PLAAT1 promotes lipid storage, as evidenced by reduced hepatic and muscular fat accumulation in PLAAT1-deficient mice.²³⁵

PLAAT2 (HRASLS2, FLJ20556)

PLAAT2 exhibits strong organelle-remodeling activity, and its overexpression in HEK293 cells results in pronounced peroxisome loss.²³⁷ Although its role in peroxisomal membrane turnover and phospholipid remodeling is less well defined than that of other family members, accumulating evidence supports a functional contribution of PLAAT2 to organelle dynamics.

PLAAT3 (PLA2G16, AdPLA, HREV107)

PLAAT3, also known as AdPLA, is a key regulator of adipose metabolism. Mice with reduced PLAAT3 expression develop severe lipodystrophy, marked insulin resistance, dyslipidemia, and increased lipolysis, highlighting its essential role in adipocyte homeostasis.²³¹,²³² In cellular systems, overexpression of PLAAT3 promotes peroxisomal degradation through its phospholipase activity.²³⁴,²³⁷ PLAAT3 also functions as a tumor suppressor by inhibiting cell proliferation and inducing apoptosis in kidney, breast, and ovarian cancers.²⁴⁴ In contrast, elevated PLAAT3 expression enhances host defense during viral infection by modulating innate immune responses.²⁴⁵ Paradoxically, the overexpression of PLAAT3 is related to progression in some cancers, including osteosarcoma, prostate cancer, HER2⁺ breast cancer, as well as metastatic lung disease, indicating its context-dependent roles in tumor biology.²⁴⁶,²⁴⁷,²⁴⁸

PLAAT4 (RARRES3, TIG3, HRASLS4, RIG1)

PLAAT4 exerts diverse immunological and tumor-suppressive functions. It acts as a chemoattractant that recruits immune cells to sites of inflammation, thereby contributing to host defense.²⁴⁹,²⁵⁰,²⁵¹ In cancer, PLAAT4 inhibits cell proliferation and promotes apoptosis in prostate, breast, and ovarian cancer cells.²⁵²,²⁵³ PLAAT4 also functions as an antimicrobial effector by restricting the growth of viruses and parasites.²⁵⁴ Through its interaction with type I transglutaminase, PLAAT4 supports epidermal barrier integrity, ameliorates keratinization disorders such as psoriasis, and reduces hyperproliferative skin lesions.²⁵⁵,²⁵⁶,²⁵⁷ In cell-cycle regulation, PLAAT4 inhibits centrosome separation and suppresses mitotic progression.²⁵⁸ Notably, PLAAT4 interacts with amyloid precursor protein and enhances microglial clearance of amyloid-β, thereby reducing amyloid plaque burden in experimental models of Alzheimer’s disease.²⁵⁹

PLAAT5 (HRASLS5, HRLP5, iNAT)

PLAAT5 regulates inflammatory responses by controlling the biosynthesis of anti-inflammatory NAEs, including palmitoylethanolamide (PEA) and arachidonoylethanolamide (AEA).²²⁹,²⁶⁰ As a Ca²⁺-independent NAT, PLAAT5 generates NAPE species that are subsequently converted into NAEs, which activate peroxisome proliferator-activated receptor-α and cannabinoid receptor 1 to suppress inflammatory gene expression. Loss of PLAAT5 markedly reduces NAE levels and exacerbates inflammatory responses, as demonstrated in toxin-induced testicular inflammation characterized by elevated IL-6, TNF-α, and inducible nitric oxide synthase expression. Restoration of PEA or AEA attenuates this inflammation, highlighting PLAAT5-derived NAEs as endogenous lipid mediators that restrain tissue inflammation and promote immune homeostasis.²⁶⁰,²⁶¹ Collectively, these features position PLAAT5 at the intersection of lipid signaling, reproductive biology, and tissue-specific lipid homeostasis.

CONCLUSION AND FUTURE PERSPECTIVES

The PLA₂ superfamily comprises a remarkably diverse group of enzymes whose functions extend well beyond their classical role as phospholipid hydrolases (Table 4). Although most PLA₂ enzymes share the capacity to cleave membrane glycerophospholipids, it is now evident that individual isoforms differ substantially in domain organization, substrate specificity, regulatory mechanisms, and downstream biological effects. These distinctions help explain how PLA₂ enzymes support essential physiological processes—such as membrane remodeling, lipid signaling, and organelle homeostasis—while also contributing to pathology when their activity is dysregulated.

Table 4. Comparison of major PLA₂ classes.

Features	sPLA2	cPLA2	PNPLA (iPLA2 family)
Typical size	Small proteins (~13–19 kDa)	Large enzymes (~85–110 kDa)	Variable, generally large (~80–150 kDa)
Dependence on Ca2+	Requires Ca2++ directly for enzymatic activity	Uses Ca2+ mainly to bind membranes and become active	Functions independently of Ca2+
Catalytic mechanism	Histidine-based catalytic center	Serine-based catalytic center	Serine-based catalytic center (patatin-like domain)
Preferred lipid substrates	Broad range of membrane phospholipids	Primarily AA–containing phospholipids	Diverse lipids, including membrane phospholipids and neutral lipids
Main biological role	Host defense, immune responses, and extracellular lipid remodeling	Controlled release of AA for lipid signaling and inflammation	Maintenance of membrane integrity, lipid balance, and organelle function
Role in inflammation	Often promotes inflammatory responses	Central regulator of inflammatory lipid mediator production	Modulates inflammation indirectly through lipid homeostasis

PLA₂, phospholipase A₂; sPLA₂, secreted phospholipase A₂; cPLA₂, cytosolic phospholipase A₂; PNPLA, patatin-like phospholipase domain-containing protein; iPLA₂, Ca²⁺-independent phospholipase A₂; AA, arachidonic acid.

Despite decades of intensive investigation, important gaps in our understanding remain. For many PLA₂ isoforms, particularly within the PNPLA, ABHD, lysosomal PLA₂, and PLAAT families, endogenous substrates and dominant functions in specific cell types have not been clearly defined. A central unresolved question is how the same enzyme can exert protective effects in one tissue yet promote inflammation, degeneration, or tumor progression in another, highlighting the importance of cellular and tissue context in shaping PLA₂ function.

Another major knowledge gap concerns the direct involvement of PLA₂ enzymes in regulated cell-death pathways, including ferroptosis, necroptosis, apoptosis, and lysosomal membrane permeabilization. Although emerging evidence links selected PLA₂ isoforms to these processes, the mechanistic relationships among phospholipid remodeling, lipid peroxidation, and execution of cell death remain incompletely understood. Elucidating how individual PLA₂ enzymes influence these pathways represents a critical research priority, particularly in the context of neurodegenerative and metabolic diseases.

From a translational perspective, progress has been constrained by the limited availability of highly selective, isoform-specific tools. Many currently available PLA₂ inhibitors exhibit incomplete specificity or off-target effects, complicating efforts to assign precise biological roles or to rigorously assess therapeutic potential. The development of selective inhibitors, targeted degraders, and activity-based probes will therefore be essential to disentangle overlapping functions and to enable robust evaluation of PLA₂ enzymes as drug targets.

Finally, emerging technologies—including advanced lipidomics, spatial transcriptomics, and organelle-resolved imaging—provide unprecedented opportunities to map PLA₂ activity with spatial and temporal resolution. Integrating these approaches with conditional genetic models will be crucial for defining when, where, and how individual PLA₂ isoforms act during disease initiation and progression.

In summary, future research should move beyond broad functional categorizations and instead focus on isoform-specific mechanisms, physiologically relevant lipid substrates, and context-dependent roles in cell fate and disease. Addressing these challenges will not only deepen our understanding of PLA₂ biology but also establish a clearer framework for targeting lipid metabolism in human disease.