CD36: bridging metabolism, inflammation, and reproduction

Abstract

Reproductive success requires coordinated regulation of metabolism and inflammation across the ovary, uterus, and placenta. CD36 is a lipid transporter and innate immune receptor that couples fatty acid handling to lipid–inflammation crosstalk. We synthesize mechanistic evidence on how CD36 regulates oocyte competence, endometrial receptivity, and signaling at the maternal–fetal interface, and how its dysregulation contributes to gestational diabetes, preeclampsia, and pregnancy loss, suggesting CD36 as a therapeutic target.

Introduction

Reproductive success requires coordinated metabolic homeostasis and immune tolerance, yet the molecular mediators linking these processes remain poorly understood, particularly in reproductive disorders. The transmembrane glycoprotein CD36, a class B scavenger receptor, has emerged as a critical player at this intersection¹. Palmitoylation sites at its N- and C-termini anchor CD36 to membrane lipid rafts, thereby facilitating its participation in signal transduction pathways². This structural diversity enables CD36 to function as a receptor for both lipid uptake and inflammatory signaling, affecting a variety of physiological processes in different tissues.

CD36 is expressed on metabolically active cells like adipocytes and myocytes, and immune cells such as macrophages, where it mediates fatty acid uptake³, lipid sensing, and mediating inflammatory responses to endogenous and exogenous ligands. Its unique structure, featuring a large extracellular domain and palmitoylated cytoplasmic tails, facilitates ligand binding and intracellular signaling, often involving pathways like peroxisome proliferator-activated receptor γ (PPARγ) activation and cooperation with Toll-like receptors⁴. While CD36’s functions in cardiovascular disease and metabolic syndrome are well-studied, accumulating evidence points to its significant roles in reproduction. In the ovary, it regulates follicular fluid lipid metabolism to maintain oocyte quality^5,6, participates in maternal-fetal lipid transport in placental trophoblast cells⁷, and affects metabolic adaptation during pregnancy⁸.

Given the prevalence of reproductive issues linked to metabolic and inflammatory disturbances, a comprehensive understanding of CD36’s mechanistic contributions is needed. In this systematic review, we critically examine the multifaceted roles of CD36 across key reproductive events, focusing on its function as a lipid sensor and inflammatory mediator in germ cells, the endometrium, and the placenta. By integrating mechanistic, animal, and clinical evidence, including insights from single-cell transcriptomics and three-dimensional culture models, this review synthesizes current knowledge on CD36-regulated pathways and identifies therapeutic opportunities for metabolic and immune-mediated reproductive disorders.

CD36 in Cellular Metabolism

Regulation of CD36 Expression and Activity

The expression and activity of CD36 are intricately regulated at multiple regulatory levels, including transcriptional regulation, signaling pathway interactions, and post-translational modifications.

At the transcriptional level, several transcription factors directly or indirectly regulate CD36 expression. For example, in chronic lymphocytic leukemia cells, signal transducer and activator of transcription 3 (STAT3), a cytokine-responsive transcription factor⁹, binds to the CD36 promoter and drives its transcription; increased CD36 expression enhances fatty acid uptake and oxidative metabolism, whereas STAT3 knockdown reduces CD36 levels and oxygen consumption, establishing a STAT3-CD36 feed-forward circuit that supports metabolic reprogramming and fatty acid oxidation¹⁰. In monocyte-derived macrophages, PPARγ, a lipid-sensing nuclear receptor that governs adipogenic and anti-inflammatory programs, transactivates the CD36 promoter through peroxisome proliferator response elements (PPREs), and the matricellular protein cartilage intermediate layer protein 2 (CILP2) further augments PPARγ-dependent CD36 transcription by acting on two PPRE motifs, thereby amplifying lipid uptake and foam-cell formation¹¹. In the diabetic heart, forkhead box O1 (FoxO1), a forkhead family transcription factor involved in glucose and lipid metabolism, does not appear to act directly on the CD36 promoter but transcriptionally upregulates the palmitoyltransferase zDHHC4, which in turn increases CD36 S-acylation and sarcolemmal localization; this FoxO1–zDHHC4–CD36 axis enhances fatty acid uptake and oxidation, promotes triglyceride accumulation, and contributes to contractile dysfunction¹².

MicroRNAs represent another critical layer of CD36 regulation. MiR-100 directly targets CD36 mRNA, thereby suppressing fatty acid uptake¹³, whereas miR-320 engages CD36 in a positive feedback loop that accelerates cardiac dysfunction associated with diabetes¹⁴.

Post-translational modifications also significantly influence CD36 activity. Notably, enhanced O-GlcNAcylation is observed in non-alcoholic steatohepatitis, which significantly upregulates CD36 expression and enhances its lipid-handling function¹⁵.

Together, these multi-layered regulatory mechanisms highlight the complexity and importance of CD36 in maintaining metabolic and inflammatory homeostasis under various physiological and pathological conditions.

Lipid Uptake and Transport Mechanisms

CD36, a critical fatty acid transporter, orchestrates lipid uptake through dynamic palmitoylation—a post-translational S-acylation of four cytosolic cysteine residues on its short intracellular tails that dictates its membrane localization and functional activity^16–19 (Fig. 1). This modification facilitates the insertion of CD36 into cholesterol-rich lipid rafts on the plasma membrane, a crucial event for its efficient interaction with extracellular fatty acids and the recruitment of downstream signaling molecules^17,18. Furthermore, palmitoylation governs the precise trafficking of CD36 through the endoplasmic reticulum (ER) and Golgi apparatus, thereby ensuring its proper insertion and positioning on the cell surface for effective lipid transport^16,17,20. Palmitoylation is dynamically controlled by palmitoyl acyltransferases, notably members of the DHHC enzyme family^17–19. These enzymes mediate both the initial membrane targeting and the maintenance of CD36 palmitoylation, conferring membrane stability ^17,19.

Fig. 1. Mechanism of CD36 palmitoylation and its regulation of fatty acid uptake and signaling in lipid metabolism.

In the ER, newly synthesized CD36 is first palmitoylated by the palmitoyl acyltransferase DHHC6, with the assistance of SelK, which enhances enzyme-substrate interaction. This initial palmitoylation facilitates CD36 incorporation into COPII-coated vesicles, a process mediated by Sar1B, and allows ER exit toward the Golgi apparatus. In the Golgi, CD36 undergoes additional palmitoylation catalyzed by DHHC4, a modification necessary for its stable sorting and progression through the secretory pathway. ARF6 regulates the post-Golgi trafficking of CD36, ensuring proper delivery to the plasma membrane. At the plasma membrane, CD36 is stabilized within Caveolin1-enriched caveolae, and its palmitoylation status is dynamically maintained by DHHC5. Upon fatty acid binding and uptake, CD36 triggers downstream signaling events:LYN is activated, phosphorylating DHHC5, which inactivates DHHC5 and thus pauses new CD36 palmitoylation; at the same time, APT1 mediates the depalmitoylation of transported CD36, causing CD36 to be dynamically released from the membrane.Concurrently, SYK is activated, which phosphorylates downstream adaptors VAV and JAK, linking fatty acid translocation to immune-metabolic signal transduction pathways.The internalized fatty acids are converted to acyl-CoA, then directed either to lipid droplets for storage or to mitochondria for fatty acid β-oxidation and energy production. CD36 Cluster of Differentiation 36, DHHC4/5/6 Asp-His-His-Cys motif-containing protein 4/5/6 (palmitoyl acyltransferases), SelK Selenoprotein K, COPII Coat Protein Complex II, Sar1B Secretion-associated Ras-related GTPase 1B, ARF6 ADP-ribosylation factor 6, LYN Tyrosine-protein kinase Lyn, SYK Spleen tyrosine kinase, VAV: Guanine nucleotide exchange factor VAV, JAK Janus kinase, ATP Adenosine triphosphate. Symbols and colors: dark green icons labeled “Palmitoyl” indicate palmitoyl groups; yellow circles labeled “Fatty Acids” indicate long-chain fatty acids; dark blue circles with a “P” indicate phosphorylation events; beige bars labeled “Caveolin1” indicate caveolin-1–enriched regions of the plasma membrane. All elements in this figure were created by the authors using BioRender.com under an academic publication license. Created with BioRender.com. Created in BioRender.R&,P). (2025). https://BioRender.com/d99r696.

Upon ligand engagement, CD36 activates intracellular signaling cascades via kinases such as LYN and SYK, effectively linking extracellular lipid sensing to key immune and metabolic responses¹⁸. The opposing process, depalmitoylation, carried out by enzymes like APT1, modulates CD36 internalization and subsequent fatty acid endocytosis. Following internalization, the acquired lipids are efficiently routed toward mitochondrial β-oxidation or directed to lipid droplet storage¹⁸.

In metabolically active reproductive tissues (such as granulosa cells, cumulus–oocyte complexes, and placental trophoblast cells), CD36-mediated lipid uptake and signaling are thought to be essential for lipid accumulation, energy provision, and maintaining-metabolic balance²¹. Through these functions, CD36 integrates nutrient sensing and cellular metabolism within reproductive microenvironments, thereby supporting gamete competence, corpus luteum function, and maternal-fetal nutrient exchange²².

CD36 in Energy Homeostasis

Beyond serving as a transporter, CD36 functions as a metabolic sensor and signaling receptor that influences gene expression and cellular pathways involved in energy homeostasis. One key mechanism is through the activation of nuclear receptors. Fatty acids imported by CD36 can bind to PPAR transcription factors, which drive the expression of genes for fat oxidation, lipid storage, and even CD36 itself²³. In fact, the CD36 gene contains PPAR response elements and is transcriptionally upregulated by PPAR activation.

In metabolically active cells, this CD36–PPAR axis helps switch the cell into a “fat-burning” mode in the presence of fats. However, if unchecked, this can result in excessive lipid uptake and accumulation, as seen in obesity and fatty liver disease^24,25. At the post-translational level, CD36 is dynamically regulated by signaling pathways that respond to nutritional and hormonal cues. Similar to the glucose transporter GLUT4, CD36 translocates between intracellular storage vesicles and the plasma membrane. Insulin stimulation triggers CD36 to move to the cell surface in muscle and adipose tissue, acutely increasing fatty acid uptake in the fed state^24,25. This movement acutely increases fatty acid uptake in the fed state. The insulin effect is mediated by elements of the insulin signaling cascade, including the kinase Akt and AS160/TBC1D1²⁶. These elements also regulate GLUT4 trafficking. In insulin-resistant states, however, this coordinated regulation becomes uncoupled: insulin-stimulated GLUT4 translocation and glucose uptake are markedly blunted, whereas sarcolemmal CD36 content and fatty acid uptake can remain inappropriately elevated or even increase, particularly in the context of lipid oversupply^26,27. This mismatch between impaired glucose transport and sustained CD36-mediated fatty acid influx favors intramyocellular lipid accumulation and the formation of lipotoxic intermediates, which further aggravate insulin resistance and contractile dysfunction in skeletal and cardiac muscle²⁸. Additionally, small GTPases like Rac1 are involved in this process^27,29. Likewise, muscle contraction during exercise activates AMP-activated protein kinase (AMPK), which independently prompts CD36 translocation to the membrane to boost fatty acid uptake for fuel^27,30. In essence, the body uses insulin, which serves as a feeding signal, and AMPK, which acts as an energy deficit signal, to acutely modulate CD36 location and activity, thereby coordinating lipid uptake with energy needs. Other factors, such as calcium signaling and the hormone leptin, have also been shown to increase CD36 translocation or expression in muscle³¹.

These diverse signaling roles illustrate that CD36 is not just a passive transporter but an active regulator of metabolic homeostasis, interfacing with hormonal and neural circuits that govern energy balance.

CD36 in Inflammation and Immune Response

CD36 serves as a Pattern Recognition Receptor

CD36 is often described as an atypical pattern recognition receptor (PRR) that works in concert with canonical PRRs³². While it can directly bind microbial components and danger-associated molecular patterns (DAMPs), CD36 usually lacks a dedicated signaling domain, so it partners with other receptors to initiate signals³³. A prime example is the cooperation between CD36 and TLR heterodimers in macrophages. Toll-like receptor-2/6 (TLR2-TLR6) heterodimers rely on CD36 to recognize certain diacylated microbial lipopeptides and lipoteichoic acid from Gram-positive bacteria^34,35. Pioneering studies showed that macrophages from CD36-null mice have impaired production of TNF-α and other cytokines in response to these TLR2/6 ligands³⁵. CD36 binds the lipid moiety of these pathogen-associated molecular patterns (PAMPs) and “presents” or concentrates them for the TLR2-TLR6 complex, facilitating TLR dimerization and downstream signaling³⁶. Likewise, TLR4-TLR6 heterodimers form a novel complex with CD36 in response to certain endogenous ligands. Macrophages or microglia lacking TLR4, TLR6, or CD36 fail to upregulate inflammatory mediators when exposed to oxidized low-density lipoprotein (oxLDL) or Aβ³⁶. Lyn recruitment is required to propagate the TLR4/6 signal, inhibiting Lyn kinase activity prevents CD36-dependent TLR4–TLR6 association and downstream cytokine induction³⁵. Beyond TLRs, CD36 also interfaces with nod-like receptor (NLR) pathways, especially the NLRP3 inflammasome. Certain CD36 ligands require intracellular processing to trigger cytosolic sensors. For example, cholesterol crystals and amyloid fibrils are internalized by CD36, which leads to their accumulation in phagolysosomes and disruption of cellular homeostasis⁴. This process can generate mitochondrial ROS and lead to assembly of the NLRP3 inflammasome complex³⁷. In this way, CD36 links extracellular DAMP recognition to the cytosolic inflammasome pathway. The end result is caspase-1 activation and maturation of IL-1β/IL-18, amplifying inflammation³⁷. Once CD36 and its partner PRRs recognize a ligand, classical innate signaling pathways are activated.

CD36-Mediated Signaling Pathways in Inflammation

CD36 is a type II transmembrane glycoprotein receptor that functions both as a transporter for long-chain fatty acids and as a PRR, capable of recognizing a variety of damage- and pathogen-associated molecular patterns (DAMPs/PAMPs) as well as oxidized lipids, thereby bridging cellular metabolism and inflammatory responses^38–43 (Fig. 2).

Fig. 2. CD36-mediated signaling pathways linking lipid metabolism and inflammation.

CD36 functions both as a long-chain fatty acid transporter and as a pattern-recognition receptor. On the left, CD36-dependent uptake of fatty acids leads to acyl-CoA formation, triacylglycerol synthesis and mitochondrial β-oxidation, which provide energy and anti-inflammatory lipid buffering and favor an M2-like, metabolically quiescent macrophage state. In the center, CD36 cooperates with TLR4/6 to sense PAMPs, DAMPs and saturated fatty acids, recruiting SFKs and MyD88 and activating the TRAF6–TAK1–MKK–JNK/p38/ERK–IKK cascade. This signaling, together with CD36-induced ROS production, activates NF-κB, which translocates to the nucleus and drives transcription of pro-inflammatory cytokines, chemokines and adhesion molecules, thereby promoting a ROS-driven M1-like inflammatory phenotype. On the right, type 2 cytokines (IL-4, IL-10, IL-13) signal through JAK–STAT3/6 to enhance PPARγ activity and PPRE-driven transcription of anti-inflammatory and metabolic regulators, stabilizing M2 polarization, whereas IFN-γ activates JAK–STAT1 and synergizes with NF-κB to reinforce M1-associated pro-inflammatory gene expression. Reciprocal inhibition between NF-κB and PPARγ establishes a CD36-dependent “switch” that balances M1-type inflammatory activation and M2-type resolution programs. CD36 Cluster of Differentiation 36, TLR4/6 Toll-like Receptors 4 and 6, PAMPs Pathogen-Associated Molecular Patterns, DAMPs Damage-Associated Molecular Patterns, FAs Fatty Acids, SFKs Src Family Kinases, MyD88 Myeloid Differentiation Primary Response 88, TRAKs TRAF-Associated NF-κB Activator Kinases, TRAF6 TNF Receptor-Associated Factor 6, TAK1 Transforming Growth Factor-β-Activated Kinase 1, MKKs Mitogen-Activated Protein Kinase Kinases, JNK c-Jun N-terminal Kinase, P38 MAPK P38 Mitogen-Activated Protein Kinase, ERK Extracellular Signal-Regulated Kinase, IKKα/β/γ IκB Kinase alpha/beta/gamma, NF-κB Nuclear Factor kappa-light-chain-enhancer of activated B cells, IκB Inhibitor of Nuclear Factor κB, p50/p65/c-Rel: NF-κB subunits, STAT1/3/6 Signal Transducer and Activator of Transcription 1/3/6, JAK Janus Kinase, PPARγ Peroxisome Proliferator-Activated Receptor Gamma, p300/CBP E1A Binding Protein p300 / CREB-Binding Protein, PPRE Peroxisome Proliferator Response Element, κB binding site NF-κB Binding Site in DNA, ACSL Acyl-CoA Synthetase Long Chain Family, ATP Adenosine Triphosphate, ROS Reactive Oxygen Species, FABP4 Fatty Acid-Binding Protein 4, LPL Lipoprotein Lipase, TAG Triacylglycerol, IL-1β/4/6/10/13: Interleukin-1 β / -4 / -6 / -10 / -13, IFN-γ Interferon-gamma, TNF Tumor Necrosis Factor. All elements in this figure were created by the authors using BioRender.com under an academic publication license. Created with BioRender.com. Created in BioRender. R&,P). (2025). https://BioRender.com/1hfdklr.

CD36-mediated fatty acid transport in inflammation and M1/M2 polarization

In macrophages, CD36-mediated lipid uptake and metabolism are critical determinants of their polarization state. Alternatively activated (M2) macrophages rely heavily on fatty acid oxidation (FAO) to meet their bioenergetic and functional demands⁴⁴. Huang et al. demonstrated that during IL-4–induced M2 polarization, triacylglycerol taken up via CD36 must be hydrolyzed within lysosomes by lysosomal acid lipase (LAL) to provide fatty acid substrates; inhibition of lipid hydrolysis or genetic deficiency of LAL markedly reduces oxidative metabolism in macrophages and impairs M2 polarization⁴⁴. Under pathological conditions, the link between CD36 and M2-like functions has also been substantiated. Tumor-associated macrophages (TAMs) in the tumor microenvironment are often enriched in lipids and express high levels of CD36, thereby acquiring an immunosuppressive M2-like phenotype through enhanced fatty acid uptake and FAO, which in turn promotes tumor growth and immune evasion^45,46. In these models, blocking FAO with etomoxir or knocking out the CD36 gene prevents TAMs from acquiring an immunosuppressive phenotype and instead enhances their pro-inflammatory activity and cytotoxicity toward tumor cells⁴⁵. Notably, abundant lipid droplets are frequently observed in M2-like macrophages and represent a hallmark of their immunosuppressive phenotype. Lipid droplets function not only as a “buffer pool” for CD36-mediated lipid transport but also as a sustained source of substrates for FAO, thereby maintaining the metabolic and functional status of M2 macrophages⁴⁶. During M2 polarization, IL-4 and IL-13 signal through JAK1/JAK3 and STAT6, inducing CD36 gene expression as part of the M2 program⁴⁷. This increases the macrophage’s capacity for phagocytosing oxidized lipids and apoptotic cells⁴³. Interventions targeting lipid droplet–associated metabolic enzymes attenuate the expression of M2 marker genes and drive macrophages toward a pro-inflammatory M1 phenotype^48,49. It is noteworthy that the reproductive tract likewise harbors resident macrophages with high phenotypic plasticity, and dynamic regulation of the local M1/M2 ratio during the implantation window and early pregnancy has been shown to be critical for embryo implantation and the establishment of maternal–fetal immune tolerance⁵⁰.

CD36-induced ROS production and its role in NF-κB activation

During CD36-mediated signal transduction, a prominent feature is the induction of intracellular reactive oxygen species (ROS) upon ligand stimulation³⁹. Specifically, CD36 forms a “signaling complex” with TLR4/6 and integrins, recruits non-receptor tyrosine kinases and Vav family proteins, and activates the MAPK pathway as well as NADPH oxidase (NOX) family members, thereby rapidly promoting ROS production^39,51. The accumulation of ROS facilitates the activation of redox-sensitive transcription factors such as NF-κB. Chen et al. further provided experimental evidence for the critical role of ROS in CD36-triggered inflammatory pathways: following phagocytosis of oxLDL, CD36 drives a shift in mitochondrial metabolism from oxidative phosphorylation toward excessive superoxide production, which in turn induces NF-κB activation and the release of pro-inflammatory cytokines³⁸. Once activated, NF-κB dimers (p65/p50) translocate into the nucleus and induce the expression of a broad array of pro-inflammatory genes, thereby amplifying the inflammatory response³⁸. The ROS–NF-κB axis is likewise considered a key molecular basis for placental development and pregnancy-related complications. Multiple studies have shown that in pathological pregnancies such as preeclampsia, villous extravillous trophoblasts exhibit marked mitochondrial dysfunction and oxidative stress; excessive ROS generation can activate NF-κB signaling, leading to upregulation of various pro-inflammatory cytokines and anti-angiogenic factors, impairment of trophoblast proliferation and invasion, and defective spiral artery remodeling, ultimately resulting in inadequate placental perfusion and maternal hypertension^52–54. It can therefore be speculated that CD36-mediated ROS generation and NF-κB activation may similarly contribute to dysregulation of the inflammatory microenvironment at the maternal–fetal interface and play a pivotal role in the pathogenesis of reproductive disorders such as preeclampsia and recurrent miscarriage.

The reciprocal interaction between CD36-regulated NF-κB and PPARγ signaling

CD36 possesses a unique “dual” functionality that enables it to simultaneously influence the balance between pro-inflammatory and anti-inflammatory signaling pathways. On the one hand, CD36 activates the ROS/NF-κB axis to promote pro-inflammatory responses; on the other hand, CD36-mediated fatty acid uptake can activate the nuclear receptor PPARγ and drive anti-inflammatory gene expression³⁹. PPARγ is a key transcription factor for the alternative activation of macrophages; it senses and binds lipid ligands, promotes the expression of M2-associated genes, and, through transrepression mechanisms, interferes with the activity of NF-κB and other pro-inflammatory transcription factors^55,56. From the perspective of CD36 function, there is an antagonistic interplay between its downstream NF-κB and PPARγ signaling: NF-κB-mediated inflammatory signaling tends to suppress the PPARγ pathway and its target genes (including CD36 itself), whereas activation of PPARγ, in turn, attenuates NF-κB-driven transcription of inflammatory genes⁵⁷. This reciprocal relationship ensures that macrophages can appropriately balance pro- and anti-inflammatory cues under different microenvironmental conditions⁵⁷. For example, in macrophages from MST1-deficient mice, impairment of the PPARγ pathway leads to reduced CD36 expression, accompanied by aberrant hyperactivation of NF-κB and robust release of pro-inflammatory cytokines. Conversely, in parasitic infection models, activation of the PPARγ–CD36 pathway enhances CD36-mediated lipid uptake and phagocytic function in macrophages, markedly upregulates the expression of antifibrotic M2 markers such as Arg1 and MMPs, while concomitantly reducing the levels of pro-inflammatory genes⁵⁷. Consistent with these observations, type 2 cytokines such as IL-4 signal through the JAK1/JAK3–STAT6 pathway to upregulate CD36 in macrophages and to enhance CD36-dependent phagocytosis of necrotic or apoptotic cells, further linking M2 programs to CD36-mediated clearance functions⁴⁷. At the maternal–fetal interface, decidual macrophages are continuously exposed to lipid ligands, type 2 cytokines and tissue remodeling signals, which suggests that CD36-regulated NF-κB and PPARγ signaling may occupy a pivotal position in fine-tuning local inflammatory tone and immune tolerance.

CD36 in Reproductive Tissues: Current Evidence and Potential Roles

CD36 in Ovary

Ovarian CD36 is strategically expressed on follicular cells and oocytes, where it influences follicle viability and facilitates key reproductive events^22,58,59.

By binding TSP-1 on microvascular endothelium, CD36 triggers endothelial apoptosis and limits new vessel growth²². In the follicle, this pathway is thought to curtail excessive angiogenesis and contribute to follicular atresia. Granulosa cell expression of CD36 rises in tandem with TSP-1 during the antral stage, precisely when follicles undergo selection or atresia⁶⁰. Loss of CD36 leads to heightened granulosa proliferation and survival. Thus, CD36 in granulosa/theca cells helps regulate the ovarian follicle pool by balancing survival and programmed atresia²².

After ovulation, granulosa cells luteinize and form the corpus luteum (CL). CD36 persists in these luteal cells, and TSP-1/CD36 signaling may influence CL angiogenesis and regression. By limiting blood vessel proliferation in the CL, CD36 could help terminate the luteal phase if pregnancy does not occur, ensuring proper cyclical regression⁶⁰. While not extensively studied, the coordinated increase of CD36 and TSP-1 right after ovulation is compatible with a role in halting angiogenesis once the CL is formed, thereby capping luteal size and function⁵⁹.

Oocytes accumulate lipids during growth, and CD36 may facilitate this. Lipid droplets and fatty acids stored within mammalian oocytes provide essential substrates for ATP production via β-oxidation and for membrane biosynthesis, and appropriate regulation of lipid metabolism is closely linked to oocyte maturation, developmental competence, and early embryo development^61,62. Conversely, chronic exposure to elevated non-esterified fatty acids or excessive intracellular lipid accumulation can induce lipotoxic stress, mitochondrial dysfunction and impaired oocyte and embryo quality⁶³. As a fatty acid transporter, CD36 on cumulus–oocyte complexes could mediate uptake of lipids. While direct evidence in mammals is limited, the presence of CD36 mRNA in oocytes implies a role in lipid metabolism of the egg⁵⁸. Consistent with a role in lipid handling, CD36 expression has been detected in mouse oocytes and shown to increase with maternal age, suggesting that CD36-mediated lipid uptake may be dynamically regulated during reproductive aging and may modulate oocyte resilience to metabolic and cryo-induced stress⁶⁴. In Drosophila, the CD36 ortholog helps deliver lipids to developing oocytes, hinting that mammalian oocytes might similarly use CD36 to import fatty acids for maturation⁶⁵. CD36 on the oocyte surface actively promotes fertilization by recognizing phosphatidylserine exposed on the sperm membrane. Its accumulation on oocyte microvilli is essential for fusion, and blocking CD36 in mouse oocytes significantly reduces the success rate of sperm-oocyte fusion and embryo formation⁵⁸.

CD36 in Uterus

The uterus, particularly the endometrium, expresses CD36 in multiple cell compartments. Human endometrial epithelium shows robust CD36 expression.

Under estrogen and progesterone in the luteal phase, stromal fibroblasts transform into decidual cells if implantation occurs. Decidual cells can sequester lipids and interact with immune cells⁶⁶. While resting stromal cells have lower CD36, decidual stromal cells (DSCs) in pregnancy upregulate metabolic genes including CD36⁶⁶. In the endometrium, CD36 is predominantly expressed on capillaries, whereas larger vessel endothelium exhibits lower levels of CD36 expression. The endometrium contains unique immune cell populations, especially in the luteal phase. Macrophage in the endometrium and in menstrual blood express CD36 as part of their phagocytic machinery^67,68. These macrophages help clear apoptotic cells during menstruation and combat infections.

During the implantation window, the endometrial epithelium becomes receptive to the blastocyst. The increased expression of CD36 in this phase suggests a role in making the endometrium “sticky” or otherwise favorable for embryo attachment. One hypothesis is that embryo adhesion is facilitated by a TSP-1–CD36 interaction⁶⁹. TSP-1 can bind to extracellular matrix and cell-surface integrins, and CD36 can serve as a co-receptor bridging these interactions⁶⁹. Additionally, cartilage oligomeric matrix protein (COMP), another receptor that was co-upregulated, works with CD36 to promote attachment, as blocking both had an additive effect⁷⁰.

Once the embryo attaches, stromal cells decidualize and maternal blood vessels remodel. CD36 may influence these processes. Decidual stromal cells loaded with lipids can modulate immune responses via CD36. A recent study showed that decidual cells releasing arachidonic acid can induce macrophages to an inflammatory phenotype through macrophage CD36 uptake, contributing to pregnancy loss in abnormal conditions⁷¹. On the vascular side, CD36 on decidual capillaries could limit excess angiogenesis, ensuring the implantation site does not over-vascularize improperly. Also, invasive extravillous trophoblasts (EVTs) from the placenta might interact with maternal CD36⁷⁰. Trophoblasts express integrins and may bind thrombospondin, maternal endothelial CD36 could then mediate anti-angiogenic signals to shape spiral artery remodeling⁷⁰.

CD36 in Pregnancy

CD36 Inflammatory Signaling at the Maternal-Fetal Interface

At the maternal–fetal interface, CD36 integrates lipid transport and pattern-recognition functions in decidual macrophages and fetal Hofbauer cells, thereby linking gestational stage–dependent metabolic and inflammatory cues to shifts in local immune tolerance and activation (Fig. 3).

Fig. 3. CD36 Inflammatory Signaling at the Maternal-Fetal Interface.

In early to mid-pregnancy (left panel), the maternal–fetal interface exhibits an anti-inflammatory phenotype, supported by high levels of progesterone and estrogen. Cytokines such as IL-4, IL-10 and IL-13 activate the JAK–STAT3/6 pathway, promoting PPARγ activity. Activated PPARγ induces transcription of CD36 via peroxisome proliferator response elements (PPRE), enhances lipid uptake, and maintains CD36^high M2-like decidual macrophages and fetal Hofbauer cells that support immune tolerance. Under late pregnancy or stress conditions (right panel)—including maternal obesity, metabolic syndrome, infection or impaired placental function—DAMPs and pro-inflammatory cytokines (e.g. IL-6, TNF-α, IL-1β) increase. CD36 facilitates TLR4/TLR6 complex formation and MyD88 recruitment, activating the TRAF6–IKK–NF-κB pathway and upregulating inflammatory gene expression, thereby promoting a shift toward M1-like inflammatory macrophages and heightened inflammatory tone. PPARγ and NF-κB signaling are reciprocally inhibitory: PPARγ suppresses NF-κB-mediated transcription through transrepression mechanisms, whereas NF-κB activation antagonizes PPARγ activity, forming a molecular “seesaw” that balances immunological tolerance and inflammatory readiness at the maternal–fetal interface. This CD36-modulated PPARγ–NF-κB axis thus serves as a critical switch between fetal-protective homeostasis and inflammation at the maternal–fetal interface. CD36 cluster of differentiation 36, DAMPs damage-associated molecular patterns, PUFAs polyunsaturated fatty acids, PPARγ peroxisome proliferator-activated receptor γ, NF-κB nuclear factor κB, PPRE peroxisome proliferator response element, JAK Janus kinase, STAT1/3/6 signal transducer and activator of transcription 1/3/6, TLR4/6 Toll-like receptors 4 and 6, MyD88 myeloid differentiation primary response 88, TRAK TRAF-associated NF-κB activator, TRAF6 tumor necrosis factor receptor-associated factor 6, IKK IκB kinase, IL interleukin, IFN-γ interferon-γ, TNF-α tumor necrosis factor-α. All elements in this figure were created by the authors using BioRender.com under an academic publication license. Created with BioRender.com. Created in BioRender. R&,P). (2025). https://BioRender.com/r3sxflr

CD36 expression on decidual macrophages supports their scavenging functions. High CD36 allows these macrophages to remove waste and release anti-inflammatory signals, which fosters a tolerant environment for the fetus⁷². In line with this, PPARγ is strongly expressed in decidual macrophages during early pregnancy and is associated with the M2 state⁷³. PPARγ not only boosts CD36 expression but also suppresses inflammatory genes, helping keep these macrophages in a regulatory mode. When PPARγ is deficient or CD36 function is dysregulated, macrophages can shift toward a pro-inflammatory M1 phenotype⁷⁴. This has been observed in recurrent miscarriage cases: decidual macrophages from women with recurrent pregnancy loss show markedly lower PPARγ and CD36 expression, and correspondingly adopt a more inflammatory profile believed to contribute to rejection of the fetus⁷³. As pregnancy progresses into mid-gestation, the decidual immune environment becomes more quiescent. Macrophages continue to perform homeostatic roles. Fetal Hofbauer cells, which are abundant in the early placenta, also remain present, although their density may decline relative to the expanding placental volume. These Hofbauer cells are generally M2-like as well, characterized by high CD36 and other scavenger receptors, and they secrete IL-10 and growth factors that support placental vasculature development⁷⁵. Thus, in normal mid/late pregnancy, CD36-expressing macrophages contribute to immune tolerance and tissue maintenance at the maternal-fetal interface.

However, in late gestation or under stress conditions, the inflammatory capacity of these CD36-expressing decidual macrophages and Hofbauer cells can be unmasked. Placental oxidative stress or elevated circulating lipids provide ligands that engage CD36 and trigger inflammatory signaling cascades. There is evident cross-talk among CD36, TLRs, and NF-κB in the context of pregnancy. Specifically, when CD36 binds certain ligands like oxLDL or saturated fatty acids, it can initiate the assembly of a TLR4–TLR6 heterodimer and recruit the adapter protein MyD88, leading to downstream activation of NF-κB^76–78. This pathway has been elucidated in macrophages. This links metabolic stress to innate immune activation and may operate at the maternal-fetal interface in conditions like preeclampsia or maternal hyperlipidemia⁷⁹. Maternal obesity offers a paradigm: obese pregnant individuals often have elevated circulating free fatty acids (FFAs), which act as endogenous ligands for TLR4/CD36 complexes. Studies have found that blood monocytes from obese pregnant women express higher levels of CD36 and TLR4, alongside increased NF-κB p65 activation, compared to lean pregnant women. This corresponds with a state of chronic low-grade inflammation⁷⁶. In the placenta, a similar phenomenon is proposed, as excess lipids or DAMPs from a stressed placenta could engage CD36 and TLR4 on decidual macrophages or Hofbauer cells, provoking NF-κB -mediated inflammation^80,81. Thus, CD36 can be a double-edged sword: necessary for routine cleanup and tolerance, but also an accessory to exaggerated inflammation when the placental environment becomes stressed.

Another layer of pathway cross-talk involves PPARγ and NF-κB in trophoblasts and macrophages. PPARγ generally acts as an anti-inflammatory modulator, and when activated, it can inhibit NF-κB signaling by sequestering NF-κB coactivators or promoting IΚBα⁸². At the maternal-fetal interface, this means that high PPARγ activity, particularly in early decidua, tends to restrain NF-κB -driven inflammation. Conversely, inflammatory stimuli that activate NF-κB can suppress PPARγ function. LPS exposure in placental trophoblast cells was shown to promote physical interaction between NF-κB p65 and PPARγ, thereby inhibiting PPARγ’s transcriptional activity and downregulating its target genes⁸³. This illustrates a feedback loop where TLR/ NF-κB activation can counteract the PPARγ-CD36 axis. In conditions of infection or stress, the balance may tip toward NF-κB, reducing PPARγ-driven CD36 expression and potentially diminishing the anti-inflammatory, lipid-clearing functions of decidual macrophages. Such cross-talk ensures that during an acute threat, the immune activation dominates over metabolic homeostasis. However, if this state becomes chronic, it may lead to sustained inflammation and impaired placental function due to insufficient PPARγ/CD36 activity. In summary, CD36 plays a multifaceted role in immune regulation at the maternal-fetal interface. Under steady-state conditions, it aids macrophages in clearing apoptotic cells and moderating inflammation, often under the guidance of PPARγ⁷³.

Beyond macrophages, emerging evidence indicates that CD36 also modulates other immune subsets that are highly relevant at the maternal–fetal interface, including regulatory T (Treg) cells⁸⁴, NK cells, and dendritic cells. In the tumor microenvironment, FoxP3⁺ Tregs upregulate CD36 to sustain fatty acid uptake, mitochondrial fitness and survival via a CD36–PPARβ–dependent program; Treg-specific Cd36 deletion selectively reduces intratumoral Treg accumulation and suppressive capacity without causing systemic autoimmunity⁸⁴. Consistently, pharmacologic activation of PPARγ enhances Treg responses by increasing CD36/CPT1-mediated fatty acid oxidation⁸⁵, suggesting that similar CD36-dependent lipid programs may support decidual Treg survival and function in pregnancy⁸⁵. CD36 has also been implicated in the lipid handling and effector function of NK cells: in colorectal cancer models, lipid-laden CD36^high NK cells show diminished cytotoxicity and reduced granzyme B/perforin expression⁸⁶, raising the possibility that analogous CD36-driven lipid accumulation could contribute to uterine NK cell hyporesponsiveness in obesogenic or inflammatory pregnancies⁸⁶. On conventional dendritic cells (DCs), CD36 mediates uptake of apoptotic cells and contributes to tolerogenic antigen presentation and peripheral Treg induction⁸⁷. Given the prominent presence of Tregs, NK cells and DCs in human decidua across gestation⁸⁸, these observations support a broader model in which CD36 shapes lipid metabolism, activation state and tolerogenic function across multiple immune lineages at the maternal–fetal interface, rather than in macrophages alone.

CD36 and Pregnancy Complications

As a multifunctional transmembrane receptor, CD36 plays a key role in the occurrence and development of various pregnancy complications by coupling dysregulated lipid handling to innate and adaptive immune activation at the maternal–fetal interface⁸⁹.

In gestational diabetes mellitus (GDM), both clinical and experimental data indicate that CD36 expression is increased in maternal metabolic tissues and in the placenta, where it enhances long-chain fatty acid uptake and triglyceride accumulation, aggravates oxidative stress, and interferes with insulin signaling, thereby contributing to systemic insulin resistance and hyperglycemia^89–91. In placentas from GDM pregnancies, trophoblasts and villous vasculature show upregulated fatty acid transporters, including CD36, accompanied by activation of NF-κB– and NLRP3 inflammasome–associated inflammatory cascades and increased production of IL-1β and IL-18, supporting a model in which CD36-driven lipid influx and ROS generation amplify sterile inflammation in the GDM placenta^92,93.

Beyond GDM, accumulating evidence suggests that CD36 contributes to placenta-mediated hypertensive disorders such as preeclampsia (PE)⁹⁴. In preeclamptic placentas, altered CD36 expression has been reported in trophoblasts and villous vasculature, together with disturbed lipid handling and endothelial dysfunction^94,95. In vitro, oxLDL–CD36 engagement in human umbilical vein endothelial cells drives mitochondrial ROS production, senescence, reduced angiogenic capacity and increased expression of inflammatory mediators, directly linking CD36-dependent lipid uptake to impaired endothelial function⁹⁴. Furthermore, thrombospondin-1–CD36 signaling has been shown to inhibit trophoblast fusion and promote a PE-like phenotype, indicating that excessive CD36 activation can disturb both vascular and trophoblast compartments of the placenta⁹⁵.

CD36-mediated inflammatory signaling is also implicated in early pregnancy loss and preterm birth^71,96,97. Recent work in humans and mouse models of miscarriage demonstrated that decidual stromal cells (DSCs) and decidual macrophages accumulate excess lipids; DSC-derived arachidonic acid is transferred to macrophages via CD36, driving mitochondrial metabolic reprogramming, ROS production and a switch toward an inflammatory M1-like phenotype that predisposes to pregnancy loss⁷¹. In line with this, altered CD36 concentrations in amniotic fluid have been associated with preterm birth, and aberrant expression patterns of CD36 and related scavenger receptors (such as CD47) have been observed in placentas from pregnancies complicated by chorioamnionitis, consistent with a role for CD36 in infection- or DAMP-driven inflammatory damage to fetal membranes and villous tissue⁹⁶. These data extend the role of CD36 beyond metabolic transport to an amplifier of local inflammatory responses that destabilize early placental and decidual homeostasis^96,97.

In terms of immune complications, pregnant women with CD36 deficiency may develop anti-CD36 alloantibodies^98,99 which, after being transferred across the placenta, can bind to fetal CD36-positive cells, inhibiting placental function and leading to fetal death, intrauterine growth restriction, or fetal hydrops¹⁰⁰. CD36 deficiency-associated fetal/neonatal alloimmune thrombocytopenia (FNAIT) is an important immune-mediated bleeding disorder that is particularly prominent in Asian populations. Mismatch in maternal and fetal CD36 status is key to triggering this immune response⁹⁹.

Taken together, these findings indicate that CD36 is not only a passive lipid transporter but also a key sensor–effector molecule that couples disordered lipid metabolism to inflammatory and immune pathways in pregnancy^71,92,94,95. At the maternal–fetal interface, CD36-dependent ROS/NF-κB and inflammasome activation, as well as its interactions with PPARγ and TLR signaling, offer a shared mechanism connecting metabolic disorders, placenta-mediated hypertensive disease, early pregnancy loss, preterm birth, and alloimmune complications^89,92,93,96. Future studies targeting CD36-dependent inflammatory signaling-for example, by modulating the CD36–PPARγ–NF-κB balance or selectively blocking pathogenic CD36 ligands or alloantibodies—may therefore represent promising strategies to prevent or ameliorate CD36-related pregnancy complications without compromising its physiological roles in nutrient transfer and tissue homeostasis^94,95.

Conclusion and Perspectives

In summary, CD36, a key molecule integrating inflammatory signaling, lipid metabolism, and reproductive regulation, is involved in multiple reproductive processes, including gamete fusion, ovarian function, placental nutrient transport, and maternal-fetal immune balance, playing an indispensable role in maintaining reproductive homeostasis. Dysregulation of its expression or function is closely associated with a variety of reproductive diseases and has become a focus of research in recent years. Although existing research has revealed the multiple functions of CD36 in the reproductive system, its molecular mechanisms remain under investigation. In the future, combining human-centered research models with cutting-edge technologies such as single-cell omics and precision intervention strategies will help further elucidate the network of CD36’s effects and promote its translational application in the diagnosis and treatment of reproductive diseases. With further research, CD36 is expected to become an important bridge between basic mechanisms and clinical practice, bringing new breakthroughs and opportunities to reproductive medicine.

Author contributions

Q.L. and D.Y. contributed equally to this work and shared the first authorship. They performed a comprehensive literature review and selected relevant articles. Q.L. drafted the initial version of the manuscript. L.D. conceived the original idea, provided critical revisions, finalized the manuscript, and secured financial support for the project. T.Y. reframed the structure, assisted with revisions, and secured financial support for the project. Y.Z. assisted with revisions and secured financial support for the project. S.C. participated in discussions, validated the selected articles, and contributed to the intellectual content of the manuscript through revisions. All authors reviewed and approved the final version of the manuscript.

Data availability

No new datasets were generated or analysed in this review. All data discussed are from previously published studies cited in the References.

Code availability

No custom code was used in this study.

Competing interests

The authors declare no competing interests.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of the manuscript, the authors used ChatGPT (OpenAI) to improve the language clarity and readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.