FABPs are a family of small (14-15 kDa) intracellular lipid-binding proteins abundantly expressed in tissues with high fatty acid metabolic activity (1). To date, 10 mammalian FABP isoforms (FABP1-9 and FABP12) have been identified, each exhibiting tissue-specific expression patterns while sharing a highly conserved tertiary structure (1). They form a β-barrel composed of two nearly orthogonal β-sheets capped by two short α-helical segments, creating an internal ligand-binding pocket that accommodates long-chain fatty acids (LCFAs) and other hydrophobic ligands (2,3). The conserved β-barrel architecture and the ligand-binding pocket common to all isoforms are illustrated in Fig. S1A, and the tissue distribution and functional grouping of the inflammation- and cancer-relevant isoforms are summarized in Table SI.

FABP isoforms differ not only in tissue distribution, but also in ligand-binding properties and intracellular functions. Liver-type FABP (FABP1 or L-FABP) is the only family member that can simultaneously bind two fatty acids or various other hydrophobic ligands due to its uniquely large binding pocket (4). By contrast, heart-type FABP (FABP3 or H-FABP), adipocyte-type FABP (FABP4 or A-FABP/aP2), epidermal-type FABP (FABP5 or E-FABP) and brain-type FABP (FABP7 or B-FABP) bind a single fatty acid with high affinity and perform distinct metabolic and signaling roles in their respective tissues (1). Notably, while FABPs were traditionally classified as intracellular proteins, studies have since demonstrated that several isoforms, including FABP4, are released extracellularly via non-classical secretion pathways and function as circulating adipokines (3,5).

Over the past two decades, metabolic and inflammatory pathways have come to be regarded as tightly integrated, a relationship for which Hotamisligil (6) introduced the term 'metaflammation' and which has since been examined extensively in relation to FABP biology (7). Chronic metabolic disorders such as obesity, type 2 diabetes and atherosclerosis are accompanied by persistent low-grade inflammation, which serves as a common substrate for the development and progression of various cancer types (3). Signaling networks such as the PI3K/AKT axis further integrate metabolic and inflammatory inputs (8). Among the molecular nodes that connect this metabolism-inflammation-cancer axis, FABPs, particularly FABP4 and FABP5, which are co-expressed in adipocytes and macrophages, have emerged as central regulators that mediate both lipid metabolism and immune responses (3,9).

FABP4 knockout mice exhibit protection against insulin resistance and atherosclerosis under high-fat diet or genetic obesity conditions, indicating that FABP4 directly contributes to the pathophysiology of metabolic disease (9,10). Furthermore, in macrophages, FABP4 coordinates cholesterol trafficking and inflammatory activity by regulating the peroxisome proliferator-activated receptor (PPAR)γ and IKK pathways (11). Elevated circulating FABP4 levels correlate not only with obesity, insulin resistance and cardiovascular disease, but also with increased risk of obesity-associated cancer types, including breast cancer (7,12). Meanwhile, FABP5 is elevated relative to matched normal tissue in several tumor types, where higher expression has generally been associated with a poorer outcome, although the reported magnitude varies by tumor type and study (13). FABP5 promotes tumor growth and metastasis by transferring ligands to nuclear receptors such as PPARβ/δ and acts as a protumorigenic factor in prostate, cervical, breast and pancreatic neuroendocrine tumors (13,14). Notably, FABP5 also regulates lipid metabolism and T cell differentiation within the tumor microenvironment (TME), suggesting that FABP functions as a metabolic-immune integrator beyond its role as a simple lipid transporter (15).

However, the role of FABPs is neither uniform nor straightforward. Within the same family, isoforms can exhibit opposite functions depending on the tissue, cell type or disease stage. For example, FABP5 supports tumor growth in several tumor types, yet in colorectal cancer (CRC) the reported direction is contested, with one study identifying it as a tumor suppressor acting through FASN degradation and autophagy, and another describing tumor-intrinsic FABP5 as growth-promoting through hypoxia-inducible factor (HIF)-1α under hypoxia (16,17). Such context-dependent duality demands cautious interpretation when approaching FABPs as singular therapeutic targets.

Previous FABP-related reviews have provided important foundations but have generally emphasized either a single isoform, a single disease category or a broad structural overview (3,7,9,13,14,18,19). This has left three practical gaps for molecular medicine. First, the same isoform can have divergent effects across cell types, for example, FABP5 in T helper 17 (Th17) cells, regulatory T cells (Tregs) and tumor cells. Second, circulating FABP4 is both a metabolic biomarker and an endocrine-like adipokine; but these two roles are often discussed separately. Third, therapeutic discussion has frequently grouped clinically observed biomarkers, preclinical inhibitors and future technologies into the same translational tier.

The present review addresses these gaps by organizing FABP biology as a context-specific evidence map across the inflammation-cancer interface rather than as a simple isoform catalogue. The primary emphasis is on FABP4, FABP5 and FABP7 as the mechanistic literature on inflammatory signaling, TME remodeling and tumor-cell plasticity is the most extensive and includes the most in vivo perturbation work. FABP1, FABP3 and FABP6 are discussed as contextual isoforms, whereas FABP2, FABP8, FABP9 and FABP12 are summarized in Table SI to avoid overextending claims beyond the available evidence.

The present review had three objectives. First, to map the isoform-specific and cell-type-specific roles of FABPs in inflammatory disease and cancer. Second, to evaluate FABPs as candidate metabolic-immune signaling integrators that may contribute to, rather than fully explain, transitions from metabolic stress to chronic inflammation and cancer. Third, to stratify clinical translation into observed biomarkers, preclinical therapeutic targets and conceptual future technologies, while highlighting therapeutic risks such as the FABP5-Treg paradox.

Earlier syntheses have addressed the FABP family from complementary angles, including metabolic and cardiovascular disease with an emphasis on FABP4 and FABP5 (3,9), peritumoral adipose tissue (18), FABP5 across tumor types (13) and the structural and ligand-binding biology of the family as a whole (1). The present review differs in scope rather than in quality of coverage as it examines the level of individual claims across isoforms, cell types and disease contexts, and reports for each claim what was measured and in what system.

The present review was prepared as a narrative synthesis supported by a structured, targeted literature search. PubMed/MEDLINE (https://pubmed.ncbi.nlm.nih.gov), Web of Science Core Collection (https://www.webofscience.com) and Scopus (https://www.scopus.com) were searched for peer-reviewed English language articles published from January 1990 to March 2026, with an emphasis on literature published after January 2020 and on landmark earlier studies that established FABP structure, knockout phenotypes, secretion biology or clinical biomarker associations. Search terms combined 'fatty acid-binding protein' or 'FABP' with individual isoforms (FABP1-FABP9 and FABP12) and disease or mechanism terms including 'inflammation', 'tumor microenvironment', 'cancer', 'adipokine', 'PPAR', 'NLRP3', 'MASLD', 'MASH', 'MAFLD', 'NAFLD', 'NASH', 'inflammatory bowel disease', 'colorectal cancer', 'psoriasis', 'skin cancer', 'breast cancer', 'biomarker' and 'therapeutic target'. Reference lists of relevant reviews and mechanistic primary articles were also screened.

Studies were prioritized if they provided the following direct mechanistic or translational evidence: i) Genetic or pharmacological perturbation of FABPs in vivo; ii) human tissue, circulating biomarkers or cohort data; iii) cell-type-specific in vitro validation; or iv) integrative reviews that clarified isoform function, ligand routing or therapeutic targeting. Conference abstracts without full peer-reviewed articles, non-English articles without accessible translations and studies lacking a direct connection to FABP biology were not considered central to the synthesis. The search aimed to support a focused conceptual review to balance breadth with mechanistic relevance, rather than to provide exhaustive enumerative coverage.

As the present article is a conceptual narrative review rather than a systematic review or meta-analysis, no prospective protocol, PRISMA flow diagram, formal risk-of-bias scoring or effect-size pooling were performed, and records of the number of items screened and excluded were not kept. Therefore, there was no attempt to express the weight of the evidence as a summary grade. A label such as 'strong' would have to be earned by studies that agree on the disease, on the cell type and on the outcome measured, and for most FABP circuits the available human association data, animal perturbation experiments and cell-based mechanistic work do not agree on all three. In place of grading, each principal claim in the present review was reported together with the system in which it was obtained, the manipulation performed, the outcome that was actually measured and the point at which extrapolation stops. Measured outcomes were kept distinct throughout and not combined, including inflammatory or immune phenotype, growth or spread of an already established tumor, premalignant change, cancer incidence and biomarker association in the absence of any perturbation. Table I sets out this mapping for the principal claims, and Table SII gives the study-level extraction from which it was built.

Section 5 (FABP networks at the inflammation-cancer interface: A context-specific evidence map) compares three disease contexts in which a preceding inflammatory or metabolic state has been linked to cancer: Metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC), obesity and breast cancer and inflammatory bowel disease (IBD) and CRC. These contexts permit comparison of where FABP-specific observations connect and where the evidence remains incomplete. They are not presented as three established FABP-mediated routes from inflammation to cancer. In the intestinal context, the inflammatory and neoplastic observations have not been experimentally connected in the studies discussed in the present review.

Section 6 (Clinical translation: Biomarkers, therapeutic targeting and readiness) distinguishes human biomarker observations, related early clinical registry records, preclinical interventions and conceptual approaches. This classification describes the setting and stage of investigation; it does not grade mechanistic certainty, clinical validity or efficacy. A common evidence grade was not assigned since the available studies differ in their biological systems, interventions and outcomes.

Although FABPs share only 20-70% sequence identity, their tertiary structures are nearly superimposable and highly conserved (20-23). The first cytosolic FABP was identified in intestinal and hepatic tissue by Ockner et al (24), and subsequent work revealed the broader physiological importance of this protein family in cellular fatty acid uptake and partitioning (25). The conserved β-barrel fold, evolutionary relationships among the 10 mammalian isoforms and their chromosomal organization are summarized in Fig. S1. All FABP isoforms are small proteins of 126-134 amino acids (14-15 kDa) that form a β-barrel composed of 10 antiparallel β-strands organized into two nearly orthogonal β-sheets (20,21). One end of the β-barrel is capped by a short helix-loop-helix motif, and the interior contains a water-filled cavity that accommodates hydrophobic ligands (4,20,26).

The gene structures of FABPs are also highly conserved. Most FABP genes consist of four exons and three introns, and several isoforms cluster within the same chromosomal region (20). For example, FABP4, FABP5, FABP8, FABP9 and FABP12 form a gene cluster on the same chromosome, suggesting that they evolved through tandem duplication of a common ancestral gene (1,27). Phylogenetic analysis indicates that the FABP family arose ~1 billion years ago, after the divergence of animals from plants and fungi, and diversified into tissue-specific isoforms through successive gene duplications (1,28,29).

Ligands are hypothesized to enter the binding pocket through the dynamic region of the β-barrel, specifically the entrance formed between α-helix II and the loops between βC-βD and βE-βF; a model termed the 'portal hypothesis' (21). The majority of FABPs bind a single LCFA (C16-C20) with high affinity and binding affinity, increasing with ligand hydrophobicity (21,30). FABP1 is a notable exception, possessing a relatively wide binding pocket that can simultaneously accommodate two LCFAs or other hydrophobic ligands such as bile acids, heme, monoacylglycerols and endocannabinoids (4,31).

FABP5 carries six cysteine residues, two of which, Cys120 and Cys127, form a disulfide bridge within the ligand-binding cavity; at present this is the only intramolecular disulfide reported among mammalian intracellular lipid-binding proteins (32). Cys120 is also the principal site at which the lipid peroxidation product 4-hydroxynonenal covalently modifies the protein, a reaction potentiated by bound fatty acid. Cells lacking FABP5 show increased 4-hydroxynonenal modification of other proteins, which has been taken to indicate a redox-buffering function (33). This evidence comes from retinal and retinal pigment epithelial tissue; whether the same function operates in epidermis has not been established directly.

FABP isoforms have historically been named after the tissues in which they were first identified or are most abundant (9,20). Currently, the 10 mammalian isoforms include FABP1 (L-FABP), FABP2 (I-FABP), FABP3 (H-FABP), FABP4 (A-FABP/aP2), FABP5 (E-FABP), FABP6 (Il-FABP), FABP7 (B-FABP), FABP8 (M-FABP/PMP2), FABP9 (T-FABP) and the more recently identified FABP12 (1,27). The numbering is not continuous, and FABP10 and FABP11 were described in teleost fish rather than in mammals (29). However, this nomenclature does not imply exclusivity of expression. In fact, most tissues express multiple FABP isoforms, which has previously caused confusion (9,34).

FABP1, FABP3, FABP4, FABP5, FABP6 and FABP7 are of relevance to the inflammation-cancer axis. FABP1 is expressed in the liver, small intestine, pancreas and kidney, and contributes to hepatic β-oxidation, bile acid metabolism and very low-density lipoprotein (VLDL) biogenesis through its unique capacity to bind two fatty acids simultaneously (4,20). FABP3 is abundantly expressed in the heart, skeletal muscle and mammary gland, where it transports LCFAs for mitochondrial β-oxidation (4). FABP4 and FABP5 are primarily expressed in adipocytes and epidermal cells, respectively, but their co-expression in immune and vascular cells, including macrophages, dendritic cells and endothelial cells, is of pathophysiological importance (3,9). Double-knockout mice for FABP4 and FABP5 exhibit more pronounced protection against insulin resistance, metabolic syndrome and various inflammatory diseases compared with single-knockout mice, indicating functional compensation between the two isoforms (4,35). FABP6 mediates ileal bile acid reabsorption and has been implicated in CRC (20). FABP7 is expressed in the brain and neural stem cells, where it regulates neurodevelopment and contributes to the maintenance of cancer stem cells in glioblastoma (GBM) and other neural tumors (1,4). Table I summarizes the principal claims by experimental system and measured outcome; Table SI provides a broader family overview.

The ligand spectrum of FABPs extends beyond LCFAs. Studies have shown that FABPs bind various bioactive lipids, including eicosanoids, retinoic acid (RA), endocannabinoids, heme, bile acids and lysophosphatidic acid (1,3). Notably, FABP5 binds RA with high affinity and delivers it to the nuclear receptor PPARβ/δ, thereby inducing genes related to cell survival (34,36). The FABP5/CRABPII expression ratio determines the fate of RA; a higher ratio directs RA toward the PPARβ/δ pathway, whereas a lower ratio favors the classical RA receptor (RAR) pathway (34,37,38). This ligand-specific partitioning mechanism provides a molecular basis for the protumorigenic role of FABP5 in cancer such as in triple-negative breast cancer (TNBC) (34,37).

The functional diversity of FABPs is expanded by their dynamic subcellular localization. Although FABPs were previously classified as cytosolic proteins, several isoforms have been shown to translocate to the nucleus and directly participate in transcriptional regulation. In particular, FABP1, FABP4 and FABP5 act as 'ligand delivery' proteins that activate PPAR family nuclear receptors under specific conditions (4,39,40). FABP4, in its ligand-bound holo form, undergoes continuous nucleocytoplasmic shuttling to transcriptionally activate PPARγ (3,41), and acts as an inter-compartmental shuttle for PPARγ agonists. Ligand binding promotes its nuclear accumulation, but its interaction with PPARγ is ligand-independent and involves both the DNA- and ligand-binding regions of the receptor (42). By contrast, FABP5 transfers RA to PPARβ/δ, a pathway closely associated with cell survival, proliferation and tumor progression (4,13).

FABP4 has been reported both to activate PPARγ and reduce its abundance. These findings are not measured on the same variable and describing them only as 'opposing' does not include information regarding the manner in which they coexist. Ligand-loaded FABP4 raises PPARγ transcriptional output (3,41). Separately, FABP4 promotes the ubiquitination of PPARγ, shifting it from mono- to polyubiquitinated forms and accelerating its proteasomal degradation. FABP4 upregulation lowers both basal and agonist-induced PPARγ transactivation, and PPARγ protein is higher in FABP4-null adipocytes (43). This is consistent with the earlier observation that PPARγ activity is elevated in FABP4-null macrophages (11).

A total of two structural observations make a single architecture plausible. The FABP4-PPARγ interaction does not require a ligand and engages regions of the receptor outside the ligand-binding domain, so binding is not conditional on FABP4 being in the holo form. Therefore, ligand binding alters the nuclear accumulation of FABP4 itself (42). The interaction also occurs through a site on FABP4 distinct from its fatty-acid-binding pocket (43). Together these data are consistent with FABP4 acting as a constitutive partner of PPARγ that both delivers the ligand to the receptor and marks it for turnover, a negative-feedback arrangement in which net transcriptional output depends on the ratio of ligand supply to receptor degradation rather than on either function alone (43). This is offered as an interpretation that accommodates the published measurements rather than as a tested model. The experiment that would test it, measuring PPARγ occupancy, transactivation and protein half-life in parallel across a range of FABP4:PPARγ ratios and ligand concentrations in a single cell system, has not been reported.

The non-classical secretion pathway of FABPs is a particularly important discovery for understanding inter-organ FABP signaling. Despite lacking a typical secretory signal peptide, FABP4 is released from adipocytes via a non-classical secretion pathway upon lipolytic stimulation or fasting (5,7). Circulating FABP4 functions as an adipokine that stimulates hepatic glucose production and impairs systemic insulin sensitivity, exerting widespread effects on distant tissues (3,5). In obese mice and humans, circulating FABP4 levels are markedly elevated and independently correlate with insulin resistance, type 2 diabetes, cardiovascular disease and an increased risk of obesity-associated cancer types, including breast cancer (7,44). Therefore, circulating FABP4 has been re-evaluated as an active signaling mediator linking the metabolism-inflammation-tumor axis, beyond its role as a mere biomarker (5).

In summary, FABPs perform a central role at the intersection of lipid metabolism and signal transduction through three layers of functional diversity: i) Binding of diverse lipid ligands via the highly conserved β-barrel structure; ii) fine-tuning of tissue-specific expression and ligand preference among isoforms; and iii) dynamic localization spanning the cytoplasm, nucleus and extracellular compartments. This molecular foundation provides the structural rationale for the divergent or convergent isoform-specific roles of FABPs in inflammation and tumorigenesis.

FABP4 has been firmly established as a representative 'proinflammatory' FABP co-expressed in adipocytes and macrophages (3,9,45); it functions as a key molecular node in metaflammation, integrating lipid accumulation, lipolysis and the production of inflammatory cytokines (7).

In macrophages, FABP4 inhibits the PPARγ/liver X receptor (LXR)α/ABCA1 axis to promote cholesterol ester accumulation and foam cell formation, while simultaneously activating the IKK/NF-κB and JNK/AP-1 pathways to upregulate proinflammatory cytokines such as TNF-α, IL-6 and MCP-1 (7,11,46,47). The transrepressive activity of PPARγ on inflammatory gene promoters, which is disrupted when FABP4 sequesters PPARγ ligands, provides an additional molecular basis for the proinflammatory consequences of FABP4 induction (48,49). Macrophage-specific FABP4 deletion induces an anti-inflammatory phenotype that confers marked protection against atherosclerotic plaque formation in ApoE-deficient mouse models (7,50). Pharmacological inhibition of aP2/FABP4 with small-molecule inhibitors similarly protects against diabetes and atherosclerosis in mouse models, providing the earliest preclinical evidence that FABP4 is a druggable target (51). Mechanistically, FABP4 uncouples lipid metabolism from inflammation by regulating mitochondrial redox signaling through uncoupling protein 2 (UCP2) (52).

Previous work has identified FABP4 as an upstream regulator of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Steen et al (53) demonstrated that loss of FABP4 in macrophages reduces oxidative modification of mitochondrial cysteine residues and upregulates antioxidant enzymes (SOD2, catalase and methionine sulfoxide reductase A). This redox rebalancing attenuates the mitochondrial unfolded protein response, thereby reducing cleaved caspase-1 and NLRP3 expression and substantially suppressing IL-1β secretion. Notably, this anti-inflammatory effect is partially reversed upon UCP2 silencing, indicating that the FABP4/UCP2 axis is a key pathway regulating mitochondrial reactive oxygen species (ROS) and inflammasome activation.

The proinflammatory activity of FABP4 has been confirmed in additional vascular contexts. In homocysteine-induced macrophage inflammation, FABP4 activates the JAK2/STAT2 pathway via Rap1a-dependent c-Src Tyr416 phosphorylation and membrane translocation; an effect negatively regulated by SOCS1 (54). Microglia, the resident macrophages of the central nervous system, also exhibit FABP4-mediated ROS and TNF-α production, JNK phosphorylation, increased Toll-like receptor (TLR) 4 expression and decreased UCP2 in response to lipopolysaccharide (LPS), all of which are reversed by genetic silencing or BMS309403 treatment (55). These findings indicate that the proinflammatory function of FABP4 is conserved across the macrophage lineage.

Moreover, FABP4 expression itself is amplified by inflammatory stimuli in a positive feedback loop, and macrophage FABP4 acts as a central hub linking endoplasmic reticulum (ER) stress, lipotoxicity and autophagy dysregulation (56,57). Palmitic acid increases macrophage FABP4 protein levels (independent of mRNA levels) via ER stress and IRE1α activation, and elevated FABP4, in turn, inhibits PPARγ and LXRα function, suppressing SIRT3, UCP2 and PGC-1α expression, and amplifying mitochondrial ROS production (58). This circuit provides a molecular basis for the mechanism by which saturated fatty acids sustain chronic low-grade inflammation in obesity.

FABP5 (E-FABP) adopts a fold that is nearly superimposable on that of FABP4 but is expressed far more widely, including in macrophages, dendritic cells and T cells (7,59). The inflammatory regulatory function of FABP5 resembles that of FABP4 in macrophages but displays a markedly more complex, context-dependent behavior in T cells.

In macrophages, FABP5 expression is induced by TLR4 (LPS) and TLR2 (zymosan) agonists (60) and has been linked to fatty acid oxidation (FAO), ROS production, inflammasome activation, IL-1β upregulation and lipid droplet formation (59,61). However, the same studies report an antitumor consequence of this activity, whereby FABP5 promotes IFN-β responses in tumor-associated macrophages (TAMs) and restricts tumor growth, and a small-molecule activator of FABP5 inhibits tumor growth in mouse models (59,61). This myeloid antitumor direction is not readily reconciled with the protumorigenic roles described for tumor-cell FABP5 below, and the two should not be summed into a single directional statement for the isoform. FABP5 also participates in cross-talk between dietary polyunsaturated fatty acid (PUFA) availability and macrophage polarization. FABP5 deletion suppresses atherosclerosis in VLDL receptor-deficient mice by reducing IL-6 and COX-2 expression and by CCR2-dependent inhibition of macrophage recruitment (62).

However, in T cells FABP5 function is far more nuanced. Li et al (63) reported that E-FABP-deficient CD4⁺ T cells exhibit markedly reduced Th17 differentiation and increased FoxP3⁺ Treg differentiation. Mechanistically, E-FABP deficiency impairs IL-6-induced expression of IL-21, RORγt and RORα while increasing PPARγ, which in turn suppresses STAT3 activity and blocks the Th17 program (63). In experimental autoimmune encephalomyelitis, FABP5-deficient mice are protected from disease through reduced Th17 differentiation (63,64). However, FABP5 expression promotes Th17 polarization in mouse models and patient samples of atopic dermatitis (65), whereas FABP5 deficiency has no effect on antigen-specific CD4⁺ or CD8⁺ T cell generation in a Listeria monocytogenes infection model (66). These divergent results illustrate that the T cell-regulatory role of FABP5 depends on stimulus, tissue context and disease stage.

From a Treg perspective, FABP5 creates one of the most important therapeutic paradoxes in the FABP field. Field et al (67) demonstrated that pharmacological or genetic inhibition of FABP5 in Tregs causes mitochondrial dysfunction, including decreased oxidative phosphorylation, impaired lipid metabolism and loss of cristae structure. These mitochondrial defects promote mtDNA release and cGAS-STING-dependent type I interferon signaling, thereby increasing IL-10 production and enhancing Treg suppressive function. Thus, the same FABP5 blockade that may attenuate Th17-driven autoimmune inflammation could reinforce immunosuppression in a tumor-bearing host.

This paradox means that FABP5 inhibition cannot be interpreted as uniformly anti-inflammatory or antitumor. The desired effect may be Th17 suppression in psoriasis, atopic dermatitis or autoimmunity, whereas the undesired oncological effect may be strengthened Treg-mediated immune evasion. Preclinical evaluation of FABP5-targeted agents should therefore include immunocompetent syngeneic tumor models, Treg depletion or rescue experiments, cell-type-specific knockout approaches and combination studies with immune checkpoint blockade before clinical translation in cancer or premalignant high-risk settings.

Not all FABPs act in a proinflammatory manner. Some isoforms attenuate inflammation under specific conditions or protect tissues from oxidative stress. FABP1 is highly expressed in the liver, small intestine and kidney, and serves as a fatty acid buffering and safe transport protein owing to its unique ability to bind two fatty acids simultaneously (4). FABP1-deficient mice display reduced hepatic β-oxidation efficiency and bile acid homeostasis disturbances. However, paradoxically, these animals can also exhibit exacerbated oxidative stress and lipotoxicity, suggesting that FABP1 functions as a 'buffer protein' that safely partitions excess fatty acids (4,68).

FABP3 (H-FABP) plays a central role in delivering LCFAs to mitochondria for β-oxidation in the heart and skeletal muscle (4). FABP3 deficiency switches cardiac fuel selection from fatty acids to glucose and induces cardiac hypertrophy in aged mice (4). During myocardial ischemia-reperfusion injury, FABP3 is rapidly released into the bloodstream and serves as an early biomarker of acute myocardial infarction (1). Recent work has shown that FABP3, FABP7 and FABP8 also bind cholesterol and facilitate its egress from lysosomes, contributing to intracellular lipid trafficking homeostasis (69). However, in the nervous system, FABP3 has been implicated in pathogenic processes such as α-synuclein aggregation and mitochondrial damage in Parkinson's disease, illustrating that even within a single isoform, tissue-specific functional divergence is pronounced (70).

These isoform-specific functional divergences indicate that a binary 'proinflammatory vs. protective' classification of the FABP family is untenable. Rather, each isoform appears optimized for the physiological demands of its expressing tissue (fuel supply, toxicity buffering and signal transduction), and the directionality of inflammation is determined when these normal functions become deregulated under pathological conditions (1).

The most recently described aspect of FABP-mediated inflammatory regulation is the existence of extracellular circulating FABP. Despite lacking a typical secretory signal peptide, FABP4 is released into the extracellular space via a non-classical secretion pathway upon lipolytic stimulation or fasting (71-73). Secreted FABP4 is a bioactive adipokine that stimulates hepatic glucose production and influences systemic insulin sensitivity in experimental models (3,5).

Circulating FABP4 levels are markedly elevated in obese humans and mice, and correlate strongly and independently with type 2 diabetes, hypertension, heart failure and atherosclerosis (5,7). Notably, circulating FABP4 is not merely a disease biomarker but an active mediator that proactively induces inflammation in distant tissues; it upregulates the ERK/JNK/STAT1 pathway and downregulates eNOS and SDF-1 signaling in human coronary endothelial cells, inducing endothelial dysfunction (74). Moreover, antibody-mediated neutralization of aP2 improves glucose tolerance and insulin sensitivity in obese mice, demonstrating that circulating FABP4 is a neutralizable therapeutic target (3,75).

The concept of circulating FABP4 supports the view of FABPs as metabolic-immune signaling integrators. FABP4 is secreted from obese adipose tissue and reaches the liver, vasculature and potentially distant TMEs to coordinate inflammation and metabolic rewiring across organs, providing an integrative framework explaining the obesity-chronic inflammation-cancer continuum. Specifically, Hao et al (12) reported that circulating FABP4 is a novel link underlying obesity-associated breast cancer development; a topic that directly connects with the role of FABPs in the TME discussed below.

A total of two features of this section carry into the next. The directionality of FABP-dependent inflammation is set by the combination of ligand, cell type and disease context, so an isoform cannot be labeled proinflammatory or anti-inflammatory on its own; and circulating FABP4 extends this biology beyond the cell in which the protein is made. The next sections examine how far these circuits operate in tumors, and where the evidence for that stops.

FABP4 has emerged as the most potent protumorigenic FABP in various obesity-associated cancer types. FABP4 is upregulated in numerous solid tumors, including breast, ovarian, prostate, hepatic, pancreatic and lung cancer, and this upregulation is generally associated with a poor prognosis (18,76,77). Dysregulated adipose-tumor crosstalk is a shared feature of these obesity-associated malignancies (78). Notably, FABP4 is expressed not only in tumor cells, but also across stromal components of the TME, including adipocytes, TAMs and endothelial cells, where it contributes to intercellular lipid exchange (19). In ovarian cancer, adipocyte-induced FABP4 expression in tumor cells promotes metastasis and carboplatin resistance (76).

The adipocyte-tumor cell fatty acid shuttle represents the most representative model of FABP4-mediated tumorigenic mechanisms and was originally delineated in the omental niche of ovarian cancer metastasis (79,80). Adipocytes supply fatty acids to tumor cells during metastasis to the omentum, inducing FABP4 expression in tumor cells and simultaneously increasing both metastatic potential and carboplatin resistance (19,76). A parallel CD36-driven fatty acid import axis, induced by adipocyte coculture, further amplifies this metastasis-initiating program (81,82). Intraperitoneal injection of FABP4-high ovarian cancer cells into FABP4⁻/⁻ mice markedly reduces tumor growth and metastasis, and FABP4 inhibitors such as BMS309403 effectively suppress both early and established metastases (76). A similar pattern is observed in breast cancer, where adipocyte cancer cell co-culture simultaneously upregulates CD36 and FABP4 expression, with their direct interaction integrally coordinating fatty acid uptake, intracellular trafficking and delivery to mitochondria and peroxisomes (82-84). This process promotes metabolic reprogramming toward FAO and is associated with adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness, in part through CD36-FABP4 interaction (84).

This model has since been tested directly and requires verification. In mice congenitally lacking mature adipocytes within the peritoneal cavity, ovarian tumors still seeded adipose-associated regions, peritoneal expansion was not impaired and the response to carboplatin was unchanged, whereas removal of the adipocyte-free omentum did reduce tumor burden (85). The earlier evidence rested on whole-body FABP4 deletion, which cannot separate adipocyte FABP4 from its expression in other compartments. Single-cell analysis of mouse and human omentum placed the highest FABP4 expression in endothelial cells. Endothelial-specific deletion reduced omental tumor expansion by ~29% during exponential growth and lowered tumor-associated vascular branching, whereas myeloid-specific deletion had no effect in this model (85). Therefore, adipocyte-derived fatty acid supply may be sufficient to support tumor growth in this niche without being required for it, and the dominant FABP4-expressing compartment appears to differ between tumor types, whereby myeloid FABP4 is required in breast models (44,86), but not in this ovarian model.

FABP4 in TAMs illustrates the mechanisms by which the inflammatory functions of immune-cell FABPs may be repurposed in the TME. Hao et al (44) reported that a CD11b⁺F4/80⁺MHCII⁻Ly6C⁻ TAM subset in breast tumors expresses high levels of FABP4, and that FABP4 in these cells is associated with activation of the NF-κB/microRNA (miR)-29b/IL-6/STAT3 axis. In the same study, FABP4 deficiency reduced mammary tumor growth and metastasis, and higher FABP4 expression was associated with poorer breast cancer survival (44). More recently, Yorek et al (86) demonstrated that unsaturated fatty acids, particularly linoleic acid, promote FABP4/CEBPα-dependent triglyceride synthesis and lipid droplet accumulation in TAMs, and that FABP4-dependent lipid mobilization in TAMs supports breast cancer cell migration and metastasis. Together, these findings support a role for FABP4-positive TAMs in metabolic crosstalk that contributes to breast cancer progression (44,86).

Circulating FABP4 may extend the fatty acid shuttle model to a systemic context. Hao et al (12) reported that obesity-associated adipose-derived FABP4 was linked to the development of distant breast/mammary tumors, suggesting a potential molecular connection between obesity and breast cancer. These observations support the possibility that the aforementioned 'FABP4 as adipokine' concept (circulating FABP4 as an adipokine) may be relevant not only to metabolic disease but also to systemic processes that influence tumor progression.

FABP5, along with FABP4, is among the most studied isoforms in cancer research. FABP5 is elevated relative to matched normal tissue in several tumor types, and higher expression has generally been associated with a poorer outcome, although the reported magnitude varies by tumor type and study (13). The protumorigenic mechanisms of FABP5 can be summarized along two main axes: i) Ligand-nuclear receptor delivery; and ii) metabolic rewiring.

The core of the ligand-nuclear receptor delivery axis is the function of FABP5 to deliver fatty acids and RA to PPARβ/δ, thereby inducing genes involved in tumor survival, proliferation and angiogenesis (VEGF, MMPs and Akt) (13,14,87). This pathway is particularly well-established in prostate cancer. In castration-resistant prostate cancer, the FABP5/PPARγ/VEGF axis progressively replaces the androgen receptor (AR)-mediated pathway, and FABP5 knockout markedly suppresses proliferation, invasion and colony formation of PC3-M cells (88). Notably, deletion of FABP5 results in a complete loss of expression of the AR splice variant ARV7, which is characterized by the absence of the ligand-binding domain. This finding highlights FABP5 as a promising target for addressing resistance to antiandrogen therapy (88).

In breast cancer, FABP5 plays a complementary role to FABP4. Both isoforms are prominently expressed in breast tissue and exhibit distinct expression patterns across molecular subtypes (19). The FABP5/CRABPII ratio is a key switch that determines the fate of RA, whereby a higher ratio directs RA toward the protumorigenic PPARβ/δ pathway, and a lower ratio favors the tumor-suppressive RAR pathway (36). Reducing the FABP5/CRABPII ratio in TNBC redirects RA from PPARβ/δ to RAR, thereby suppressing tumor growth (38).

Along the metabolic rewiring axis, FABP5 shows tight connections with FASN and hypoxia signaling. In cervical cancer, FABP5 facilitates lymph node metastasis by reprogramming fatty acid metabolism, which correlates with elevated MMP-2 and MMP-9 expression (89,90). In pancreatic neuroendocrine tumors, FABP5 interacts directly with FASN, modulating its stability via the ubiquitin-proteasome pathway and activating the WNT/β-catenin signaling cascade to promote tumor progression (91). Notably, the direction of this coupling is the opposite of that reported in colorectal cells, where FABP5 stabilizes FASN in pancreatic neuroendocrine neoplasia, but promotes its ubiquitination in CRC (16,91). The two reports come from the same group and appeared within weeks of each other, share the same interaction partner and ubiquitin-proteasome read-out and neither addresses the other. Rather than a contradiction, this is the clearest available indication that the FABP5-FASN relationship is tumor-type dependent and cannot be stated as a single rule.

Reports on FABP5 in CRC have opposing results, and the discrepancy is informative rather than incidental. Seo et al (17) showed that transient FABP5 silencing lowered hypoxia-induced HIF-1α protein and its target transcripts (VEGF, CA9, LOX, PDK1 and BNIP3L) in HCT116 and WiDr cells, and that FABP5-silenced HCT116 spheroids grown on an oxygen-permeable three-dimensional chip remained smaller than the controls over 7 days. Ye et al (16), also working with the HCT116 cell line, reported the converse, whereby FABP5 protein was lower in 90 paired colorectal carcinoma specimens than in adjacent tissue, higher FABP5 was associated with longer survival, stable FABP5 overexpression suppressed proliferation, migration and xenograft growth while stable knockdown enhanced them, and the effect was traced to FABP5-dependent ubiquitination of FASN with downstream inhibition of mTOR and induction of autophagy.

These are four differences between the two studies which may account for the discrepancies; however, none have been further studied. First, the lesions differ, whereby the paired expression series analyzed by Seo et al (17) (GSE8671) comprised colorectal adenomas, while Ye et al (16) sampled established carcinoma. Therefore, the two tissue observations may describe different points on the adenoma-carcinoma sequence, rather than opposite findings in the same lesion. Second, the analytes differ, with transcript vs. protein. Third, oxygen tension is central to one mechanism and absent from the other, in which the FABP5/HIF-1α axis was defined under hypoxia and in spheroids that develop an internal hypoxic region, whereas the FASN/mTOR/autophagy axis was characterized in normoxic monolayers and subcutaneous xenografts. Fourth, the perturbations differ in kinetics and in direction, with transient silencing in one case against stable overexpression and knockdown in the other; only the latter tested both directions, and no in vivo experiment has been reported for the HIF-1α arm.

A third report adds a distinct axis rather than adjudicating between these two. In colorectal cells, p53 induces FBXO2, which binds FABP5 and directs it to chaperone-mediated autophagy. The resulting fall in PUFAs reduces lipid peroxidation and confers resistance to ferroptosis; arachidonic acid (AA) supplementation reverses it (92). FABP5 sensitizes cells to ferroptosis, which again places it on the tumor-restraining side, although the outcome measured is ferroptosis susceptibility rather than proliferation and the in vivo arm manipulated FBXO2 rather than FABP5. Therefore, two of the three colorectal reports describe a restraining role, but the one that does not was conducted under hypoxia and in three-dimensional culture, so oxygen tension remains the most testable candidate for the discrepancy.

Neither direction of the FABP5 effect is therefore treated as established across CRC. A comparison using the same colorectal cell models, bidirectional FABP5 perturbation and matched oxygen conditions, with FASN, HIF-1α and autophagy assessed in parallel, could test whether oxygen tension or pathway interactions explain the discrepancy. Stage-matched human tissue would address the separate question of disease-stage associations. These explanations remain untested.

In cervical cancer, FABP5 promotes EMT, lymphangiogenesis and lymph node metastasis by reprogramming fatty acid metabolism. This includes FABP5-driven lipolysis and de novo fatty acid synthesis which increase intracellular fatty acid levels that activate the NF-κB signaling pathway and FABP5 expression, which independently predicts lymph node metastasis and poor prognosis (90). Additionally, FABP5 serves as an intracellular carrier of anandamide and related N-acylethanolamines in the brain, delivering them to fatty acid amide hydrolase for hydrolysis, such that pharmacological FABP inhibition elevates brain anandamide levels and produces analgesia (93). From the perspective of antitumor immune evasion, FABP5 illustrates the manner in which the aforementioned Treg-regulatory function is exploited oncologically. In tumor-infiltrating Tregs, FABP5 inhibition activates the mtDNA leakage cGAS/STING/IL-10 pathway, paradoxically enhancing the Treg immunosuppressive function (67). This raises a fundamental dilemma in the clinical application of FABP5 inhibitors in autoimmune disease (where inhibition is beneficial) vs. cancer (where inhibition may reinforce immunosuppression). Meanwhile, in CD8⁺ T cells, FABP5 promotes linoleic acid uptake and induces ROS-mediated T cell death, thereby reducing TME CD8⁺ T cells and accelerating tumor growth under high-fat-diet conditions (15,94).

FABP7 (B-FABP) is the most studied FABP in nervous system tumors, including GBM. In the normal brain, FABP7 functions as a marker for radial glial cells and neural stem cells and is essential for establishing the radial glial fiber system during neurogenesis (95,96). The transformation of this normal neurodevelopmental role into the maintenance of 'cancer stemness' in oncological contexts is a unique mechanism of FABP7.

Although FABP7 is predominantly expressed in neural lineage tissues, aberrant FABP7 expression has also been reported in breast cancer subtypes, where its subcellular localization correlates with clinical outcomes (97). FABP7 is most characteristically associated with GBM stem-like cells (GSCs). FABP7 is highly enriched in patient-derived GSCs and localizes to both the cytoplasm and nucleus (98). Differentiation of GSCs by serum addition markedly reduces FABP7 expression, and FABP7⁺Sox2⁺ tumor cells are significantly increased in WHO grade IV GBM compared with grade II and III tumors (98). siRNA-mediated FABP7 downregulation reduces both proliferation and migration of GBM-derived neurospheres, and FABP7 expression increases after radiation, suggesting an association with radioresistance (99). This behavior places FABP7 among the lipid-handling mediators that contribute to immune evasion by cancer stem cells (100).

Mechanistically, recent work has demonstrated that FABP7 delivers PUFAs to the nuclear receptor retinoid X receptor (RXR)α, activating a PUFA/FABP7/RXRα neurogenic pathway (96). This pathway induces SOX2 (a key stemness regulator) and ZEB1 (an EMT transcription factor), driving the 'stationary-to-migratory' transition in GSCs (96). Notably, the role of FABP7 is bidirectional depending on the fatty acid microenvironment. In an AA-rich environment, FABP7 promotes GBM growth and infiltration, while in a docosahexaenoic acid (DHA)-rich environment, FABP7 may inhibit tumor infiltration through increased DHA uptake and utilization (101). Therefore, FABP7 has been proposed as a candidate vulnerability of GBM neural stem-like cells, suggesting that FABP7-targeted therapy may need to be combined with manipulation of the ligand environment (101).

Limitations in FABP7 inhibitor development have also been noted, as the existing drug SBFI-26 displays low selectivity, targeting both FABP5 and FABP7, and its blood-brain barrier permeability has not been evaluated (102). This underscores the need for isoform-selective and tissue-specific FABP inhibitors.

FABP1 (L-FABP) shows opposing roles in liver and CRC depending on tissue context. In some HCC cases, FABP1 promotes tumor growth and angiogenesis by upregulating VEGF-A through the VEGFR2/Akt/mTOR pathway (103), whereas in another study, FABP1 expression is downregulated in poorly differentiated HCC and associated with poor prognosis (104). In CRC, FABP1 has been reported as a differentiation marker downregulated at the adenoma stage but is upregulated again in advanced cancer (1). Such stage- and context-dependent expression changes indicate that FABP1 cannot be classified simply as a tumor-promoting or -suppressing factor. Therefore, FABP1 and FABP6 exert mechanistically distinct gastrointestinal effects, whereby FABP1 modifies tumor cell phenotype in a stage-dependent manner through cell-intrinsic lipid buffering, whereas FABP6 contributes through an epithelial bile acid-microbiota interaction that is more clearly tied to chronic intestinal inflammation. Both isoforms are summarized alongside FABP4/FABP5/FABP7 in Table I, which states for each claim the system in which it was obtained, the outcome measured and what remains untested.

A total of two points from this section are relevant to the subsequent discussion. FABPs act both within tumor cells and in the surrounding compartments, and the compartment that matters is not fixed, as it differs between tumor types. As the same isoform can alter tumor metabolism and immune function in opposite directions, antitumor and immunomodulatory effects must be assessed separately rather than assumed to align.

As aforementioned, across these disease contexts, FABP isoforms appear to converge on four recurring signaling modules and are summarized in the present review to highlight cross-context recurrence rather than to re-describe individual mechanisms. First, FABP-nuclear receptor routing links lipid availability to transcriptional programs, whereby FABP4 interacts with PPARγ-related signaling, FABP5 can route RA or fatty acids toward PPARβ/δ and FABP7 can regulate ligand-dependent RXRα signaling (13,34,41,43,96). Second, inflammatory cytokine modules involving NF-κB, IL-6 and STAT3 recur in macrophage and TAM contexts (11,44,124,125). Third, mitochondrial metabolism, ROS and inflammasome activation connect lipid chaperoning with innate immune activation (53,67). Fourth, hypoxia-linked metabolic rewiring has been described for FABP5 and HIF-1α in hepatic and CRC cells (17,126). In colorectal cells this has been shown under hypoxia and in three-dimensional culture, without in vivo confirmation, and it coexists with a report of the opposite direction under normoxia (16); it should therefore be read as a condition-specific observation rather than a general property of FABP5 in this tumor type.

These convergent modules provide a mechanistic rationale for the model in Fig. 3, but they should be interpreted as context-dependent routes rather than universal FABP-driven cascades. In some settings, FABPs appear causal, in others, they are modifiers or may serve mainly as biomarkers of metabolic or inflammatory stress.

Synthesizing these observations, Fig. 3 presents them as a conceptual framework. Fig. 3A involves lipid and metabolic stress, including obesity, lipotoxicity, bile acid exposure or cutaneous lipid stress, which may induce tissue-specific FABP expression, including FABP4 in adipose tissue and macrophages, FABP1/FABP4 in the liver, FABP6 in the ileum and FABP5 in skin. Fig. 3B involves the regulation of inflammation, whereby selected FABPs can amplify inflammatory signaling through PPAR-dependent, NF-κB-linked or inflammasome-related pathways, with circulating FABP4 providing a systemic adipokine route. Fig. 3C involves epithelial and tumor-cell adaptation, whereby FABP-linked lipid routing and nuclear receptor signaling may support survival, stemness or plasticity of stressed epithelial or tumor cells. Fig. 3D involves TME interactions, whereby FABP4/5/7-related circuits may support fatty acid shuttling, immune evasion, TAM activity, Treg function or tumor-cell plasticity.

The clinical implication is not that FABP targeting is already a validated stage-specific therapy, but that the stage of disease, dominant cell type and immune context should determine the manner in which FABP biomarkers or inhibitors are tested. FABP4 inhibition for MASLD/MASH-HCC prevention, FABP5 inhibition for Th17-driven inflammation or selected PPARβ/δ-driven tumors and FABP7 targeting for neural-lineage tumor plasticity are testable hypotheses rather than clinical recommendations.

FABP4 is the most developed circulating FABP biomarker, and also the most difficult to interpret. Serum FABP4 is consistently associated with obesity, insulin resistance, type 2 diabetes and cardiovascular disease (5,7,127-132), which makes it a useful index of systemic metabolic-inflammatory burden, but limits its specificity for cancer.

A total of three directional questions must be distinguished, since conflating them would allow an association that is downstream of adiposity to be read as evidence that FABP4 contributes to cancer. First, adiposity is a cause of higher circulating FABP4 rather than the reverse, as shown by Mendelian randomization of body mass index against the plasma proteome (123); therefore, an elevated level is in part a consequence of the adipose state it is being used to interrogate. Second, whether the tumor itself raises circulating FABP4 has not been established. Levels fall after radical resection in CRC (118), which is compatible with a tumor contribution but is equally compatible with the effects of surgery, of resolving inflammation and of altered metabolic state. Third, the circulating protein and tissue FABP4 are different compartments, and genetic epidemiology of the former does not speak to the latter.

Where the causal question has been tested directly, the result was null. Neither measured nor genetically predicted circulating FABP4 was associated with CRC risk in a prospective analysis of 1,324 incident cases combined with two-sample Mendelian randomization in 58,131 cases (119). That analysis was powered to detect an odds ratio of ~1.17/standard deviation. Therefore, a small effect is not excluded, but a large causal contribution is.

Tissue FABP5 and FABP7 are more effectively supported as expression markers than as circulating ones, and both remain exploratory pending standardized assays and independent cohorts (13,14,87-90,96-102); for FABP5 the prognostic direction is contested in CRC (Table I). FABP3 and FABP1 have established roles in myocardial and renal or hepatic injury (133-139), but this established biomarker status does not extend to oncological applications.

BMS309403 remains the best-characterized small-molecule FABP inhibitor, although it engages the binding pockets of FABP3, FABP4 and FABP5 rather than FABP4 alone (140-143). In mouse models it improves atherosclerosis and endothelial function, reduces ovarian cancer burden and carboplatin resistance, prevents progression from steatohepatitis to HCC, and reduces FABP4-dependent CD8⁺ T-cell senescence in adipocyte-rich tumors (51,76,111,142,144-147). As the compound is not isoform-selective, none of these results attributes the effect to a single FABP with confidence.

FABP4-neutralizing antibodies are mechanistically distinct as they act on the extracellular pool while leaving intracellular FABP4 intact (3,75,112,148). SBFI-26 and related compounds are the main tools for FABP5 and FABP7, but their limited selectivity between those two isoforms, and the absence of independently confirmed blood-brain barrier penetration, mean that the reported effects in prostate cancer and GBM are proof of concept rather than isoform-specific validation (14,102).

Intervening on FABP5 in an immune context requires particular caution. Acute loss of FABP5 function in Tregs increases IL-10-dependent suppressive capacity in vitro, which would be an unwanted effect in a tumor-bearing host (67). That finding rests on a single primary report, whereby its pharmacological arm used the aforementioned non-selective inhibitor, and FABP5 was not perturbed in vivo in tumor-bearing animals; independent replication is the first requirement.

Isoform selectivity is the most fundamental barrier. FABP3, FABP4, FABP5 and FABP7 share a conserved β-barrel and partially overlapping ligand pockets. Therefore, complete selectivity is difficult, and dual or pan-FABP inhibition risks disrupting cardiac FAO, hepatic lipid buffering, epithelial barrier function or neural lipid handling (1,143).

Compensation between isoforms is a distinct problem and not confined to the FABP4-FABP5 pair. FABP5 rises when FABP4 is deleted in adipocytes yet does not substitute for it in macrophages (3,35,76). In Tregs, FABP4/FABP5 double-knockout cells show a metabolic phenotype opposite to that of acute pharmacological inhibition, attributed to compensatory FABP3 (67). Therefore, germline deletion and acute inhibition are not interchangeable read-outs, and a target validated by one may behave differently under the other.

Delivery separates the strategies, whereby antibody-mediated neutralization reaches only the extracellular pool, whereas intracellular FABP5 or FABP7 targeting requires exposure inside tumor or immune cells, with central nervous system penetration decisive for GBM and hepatic exposure for metabolic liver disease.

Safety is structural rather than incidental, whereby FABPs are homeostatic lipid chaperones, not cancer-specific oncoproteins, and sustained inhibition could alter PPAR signaling, mitochondrial fuel selection, lipid storage, barrier function or immune-cell differentiation.

The limitations of isoform selectivity, delivery and safety require the target isoform, target cell and disease context to be defined before an agent is tested. Antitumor effects should be measured together with immune and metabolic consequences in the same experimental system.

The FABP5-Treg paradox should be treated as a design principle rather than a minor caveat. Desired anti-inflammatory effects, such as Th17 suppression, may conflict with antitumor immunity if FABP5 inhibition enhances IL-10-producing Tregs. Conversely, FABP4 inhibition may restore exhausted or senescent CD8⁺ T-cell function in adipocyte-rich tumors (147). These opposing immune effects require preclinical testing in immunocompetent systems, with cell-type-specific FABP deletion, Treg depletion/rescue and immune checkpoint combinations before human cancer studies.

It has not yet been elucidated in which tissues and under what conditions inter-isoform compensation operate, and whether compensatory upregulation limits the durability of therapeutic inhibition. This can only be addressed with conditional tissue-specific deletion and simultaneous silencing of more than one isoform. At present, whether the less-studied FABP9 and FABP12 can substitute in any context remains unknown (1).

Existing FABP research has predominantly been conducted at the bulk tissue level, failing to capture heterogeneity in cell-by-cell FABP expression within the same tissue. However, recent single-cell RNA sequencing studies have revealed notable differences in FABP expression by cell subpopulation. For example, only the CD11b⁺F4/80⁺MHCII⁻Ly6C⁻ subpopulation of TAMs in breast cancer highly expresses FABP4 (44), and only the CD8⁺ T cell subpopulation adjacent to the adipocyte-rich microenvironment in ovarian cancer exhibits the FABP4-mediated senescence phenotype (147). Single-cell analysis of GBM has revealed notable differences in FABP7 expression between tumor core and infiltrating margins (102).

This cell subpopulation-level FABP heterogeneity provides an opportunity to refine the 'inflammation-cancer continuum' model with spatial and temporal resolution. At present, integrated single-cell RNA sequencing analysis pipelines enable unified comparison of FABP expression patterns across disease contexts (149), and the rapid maturation of spatial transcriptomics technologies (150,151) provides an unprecedented opportunity to map FABP-mediated niches. Multicellular program discovery approaches such as DIALOGUE (152) could be particularly powerful in identifying coordinated FABP-driven states across adipocytes, macrophages and tumor cells. Future research should capture the spatial distribution of FABP⁺ cells within the TME, interaction patterns with neighboring cells and dynamic changes during treatment response through spatial transcriptomics and multiplex protein imaging techniques such as CODEX/MIBI. Such data will form the foundation of patient stratification and precision FABP-targeted therapy.

The aforementioned FABP6/bile acid/microbiota axis is an actively expanding emerging area of FABP research. The intestinal dysbiosis-exacerbated colitis phenotype in Fabp6ΔIEC mice (116) suggests that FABPs may participate in host-microbe interactions, extending their role beyond intracellular lipid handling. However, this axis is not limited to FABP6. FABP4 may also be involved in the systemic circulation of microbial metabolites (short-chain fatty acids and lipopolysaccharides) through intestinal lymphatics and adipose tissue, and FABP5 may be a link between cutaneous microbiota changes and psoriasis progression (153).

Causal evidence from humanized gnotobiotic models demonstrates that gut microbiota from obese hosts is sufficient to transmit metabolic phenotypes (154), and microbial metabolites have been established as central mediators of host-microbiota communication (155,156). Bile acid derivatives have been shown to directly control the Th17/Treg axis, which is also central to FABP5 biology (157). Future research should address: i) Which microbial metabolites act as ligands for each FABP isoform; ii) the mechanisms by which gut microbiota composition regulate FABP expression and function; and iii) whether probiotics, prebiotics or fecal microbiota transplantation can modulate FABP-mediated inflammation-cancer pathways. A study by Kwon et al (116) demonstrated alleviation of colitis in Fabp6ΔIEC mice through oral administration of L. murinus, which represents the first practical example of such microbiota-mediated modulation of the FABP pathway and suggests the possibility of therapeutic strategies combined with dietary interventions.

Interface-directed inhibition, targeted protein degradation, selective delivery and artificial intelligence-assisted structural analysis are possible research approaches (158-165). The cited technology literature motivates their consideration but does not, by itself, establish FABP-specific target engagement or antitumor efficacy. Predicted binding requires biochemical and cellular validation, followed by appropriate in vivo exposure and safety studies. These approaches are therefore discussed as future research directions.

Finally, emerging evidence suggests that FABP function may extend beyond the aforementioned inflammation-cancer continuum. The role of FABP4 as an aging biomarker (168), together with observations that other FABP isoforms participate in neural and behavioral regulation (1,70), hints at broader biological roles. These emerging dimensions intersect with the metaflammation framework, particularly via the concept of inflammaging in obesity-associated endocrine dysfunction. Further investigation of the FABP network as a common molecular substrate of metaflammation and inflammaging represents a logical extension of the aforementioned framework.