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Review Open Access

Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review)

  • Authors:
    • Young-Sool Hah
    • Young-Tae Ju
    • Seung-Jun Lee
    • Jeongyun Hwang
    • Seung-Jin Kwag
  • View Affiliations / Copyright

    Affiliations: Department of Surgery, Institute of Medical Science, Gyeongsang National University College of Medicine, Jinju, Gyeongsangnam 52727, Republic of Korea, Department of Convergence Medical Sciences, Gyeongsang National University, Jinju, Gyeongsangnam 52727, Republic of Korea
    Copyright: © Hah et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 366
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    Published online on: November 4, 2026
       https://doi.org/10.3892/ijmm.2026.6037
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Abstract

Fatty acid‑binding proteins (FABPs) comprise ten mammalian isoforms (FABP1‑FABP9 and FABP12), each a small intracellular lipid chaperone traditionally viewed as a mediator of fatty acid uptake, trafficking and metabolic partitioning. Evidence from metabolic disease, immunology and oncology indicates that selected FABP isoforms also regulate inflammatory signaling, immune‑cell metabolism and tumor‑stromal crosstalk. Prior reviews have mainly emphasized single isoforms of FABPs or single disease categories. The present narrative review organized FABP biology as a context‑specific evidence map across the inflammation‑cancer interface, in which each principal claim is reported together with the experimental system, with the outcome and limits of extrapolation described. The main mechanistic focus was FABP4, FABP5 and FABP7. The structural determinants of isoform specificity, ligand routing to nuclear receptors and the non‑classical secretion of FABP4 as a circulating adipokine were summarized. The evidence supports a model in which FABPs may contribute to, rather than fully explain, the progression from metabolic stress to chronic low‑grade inflammation, premalignant remodeling and the establishment of the tumor microenvironment. In the present model, FABP4 links adipocytes, macrophages, endothelial cells and tumor cells through fatty acid shuttling and inflammasome/cytokine signaling; FABP5 connects retinoic acid and peroxisome proliferator‑activated receptor β/δ signaling with tumor‑cell growth and T helper/regulatory T‑cell balance; and FABP7 regulates neural‑lineage tumor plasticity through ligand‑dependent retinoid X receptor α signaling. In addition, translational evidence was stratified into clinically observed biomarkers, preclinical therapeutic targets and conceptual future technologies. Particular attention was paid to biomarker confounding by obesity, diabetes, age and sex, and to the therapeutic paradox in which FABP5 inhibition may suppress T helper 17 cell‑driven inflammation while enhancing regulatory T‑cell‑mediated immunosuppression in cancer. This synthesis provides a restrained conceptual framework for stage‑, isoform‑ and cell‑type‑specific FABP research.
View Figures

Figure 1

Isoform- and context-specific roles
of FABPs in inflammation. (A) FABP4 in the macrophage. Palmitic
acid induces ER stress and IRE1α activation, stabilizing FABP4
(56-58). FABP4 suppresses UCP2, raising
mitochondrial reactive oxygen species and priming the NLRP3
inflammasome for IL-1β release (52,53), and activates IKK/NF-κB and
JNK/AP-1 to increase TNF-α, IL-6 and MCP-1 (7,11,46,47). This circuit has been described in
atherosclerotic plaque macrophages (11,48,50), obesity-associated metabolic
inflammation (3,9,10) and microglia (55). (B) FABP5 and T-cell fate,
reported here in three separate evidence layers. Observed:
Tumor-infiltrating Tregs express high FABP5, and tumor interstitial
fluid is lipid-poor (67).
Functional experiment: Acute loss of FABP5 function in
differentiated Tregs, by BMS309403 (which engages FABP3, FABP4 and
FABP5) or by FABP5 knockdown, impairs mitochondrial integrity and
triggers mtDNA release, cGAS-STING-dependent type I IFN signaling
and IFNAR-dependent IL-10 production, increasing suppressive
capacity in vitro (67).
Not yet tested: whether lipid scarcity phenocopies this in
vivo, and the net effect on antitumor immunity. On the left,
IL-6/STAT3/RORγt-driven FABP5 supports Th17 differentiation in
autoimmune and atopic settings (63-65,153,166). Not shown: In macrophages, FABP5
activity has instead been reported to restrict tumor growth through
IFN-β (59,61). Candidate agents are listed in
Table II. Arrows and symbols:
Solid black, direction of signaling or of a downstream consequence;
blunt-ended connector, inhibition (pharmacological inhibition or
knockdown of FABP5); cross on UCP2 in (A), FABP4-dependent
suppression of UCP2. AP-1, activator protein 1; cGAS, cyclic
GMP-AMP synthase; ER, endoplasmic reticulum; FABP, fatty
acid-binding protein; IFNAR, IFN α/β receptor; IKK, IκB kinase;
IRE1α, inositol-requiring enzyme 1α; MCP-1, monocyte
chemoattractant protein 1; mtDNA, mitochondrial DNA; NLRP3, NLR
family pyrin domain containing 3; RORγt, retinoic acid
receptor-related orphan receptor γt; ROS, reactive oxygen species;
STING, stimulator of interferon genes; Th17, T helper 17; Treg,
regulatory T cell; UCP2, uncoupling protein 2.

Figure 2

Isoform-specific contexts in cancer.
Three contexts are shown separately since the evidence does not
support a single shared pathway. (A) FABP4 acts in more than one
compartment, and which one dominates differs by tumor type.
Cancer-associated adipocytes and FABP4-high TAMs supply FAs to
tumor cells, and the TAMs also supply IL-6 (44,79,80,86); within tumor cells CD36-mediated
uptake feeds FABP4, which partitions FAs to β-oxidation and lipid
droplets (84). However, in the
omental niche, mature adipocytes are not required for ovarian tumor
growth. Endothelial cells are the principal FABP4-expressing
population and endothelial-specific deletion reduces tumor
expansion and angiogenic branching whereas myeloid-specific
deletion does not (85). (B)
FABP5 in tumor cells. FABP5 delivers RA and FAs to PPARβ/δ-RXRα,
inducing survival and proliferation genes, whereas RA routed
instead to CRABPII-RAR activates a growth-inhibitory program; the
FABP5:CRABPII ratio sets which of the two receptors the ligand
reaches, and lowering it suppresses tumor growth in mammary
carcinoma models (13,14,34,36-38,87). In colorectal cancer the reported
direction is contested (Table
I). (C) FABP7 in glioblastoma. FABP7 delivers PUFAs to RXRα,
inducing SOX2, ZEB1 and CD44 and supporting proliferation and
migration of GSCs; arachidonic-acid-rich and
docosahexaenoic-acid-rich environments have opposite effects
(96,101). This has been demonstrated in
GSCs and has not been tested in premalignant lesions of other
tissues. Arrows and symbols: Solid black, release of FAs from
adipocytes and macrophages in (A), movement of RA in (B) and
downstream transcriptional or phenotypic output in (B) and (C);
dashed orange, uptake or intracellular movement of FA; solid orange
in (C), delivery of PUFAs to RXRα; solid red in (A), IL-6
signaling; dashed black in (C), an outcome conditional on the
surrounding lipid composition; dashed red blunt-ended connector in
(C), suppression of that outcome; balance symbol in (B), the
FABP5:CRABPII ratio that determines which receptor the ligand
reaches. CRABPII, cellular retinoic acid-binding protein II; EMT,
epithelial-mesenchymal transition; FA, fatty acid; FABP, fatty
acid-binding protein; GSC, GBM stem-like cell; PPARβ/δ, peroxisome
proliferator-activated receptor β/δ; PUFA, polyunsaturated fatty
acid; RA, retinoic acid; RAR, retinoic acid receptor; RXRα,
retinoid X receptor α; TAM, tumor-associated macrophage; ZEB1, zinc
finger E-box binding homeobox 1.

Figure 3

Domains in which FABPs have been
implicated at the inflammation-cancer interface. The four domains
are shown as related areas rather than as sequential stages, as the
evidence does not establish a single ordered progression. Solid
connectors mark links supported by perturbation experiments; dashed
connectors mark links that have not been directly tested. (A) Lipid
and metabolic stress. Obesity, high-fat diet, hepatic steatosis,
bile acid exposure and cutaneous lipid stress are associated with
tissue-specific FABP induction: FABP4 in adipose tissue and
macrophages, FABP1 and FABP4 in liver, FABP6 in the ileum and FABP5
in skin. Principal mediators are free fatty acids, bile acids and
damage-associated molecular patterns. (B) Regulation of
inflammation. FABP4 amplifies NF-κB-linked cytokine production and
UCP2-dependent inflammasome activation, circulating FABP4 acts at a
distance as an adipokine, and FABP5 influences the Th17/Treg
balance. (C) Epithelial and tumor-cell adaptation. RA is
partitioned between FABP5-PPARβ/δ and CRABPII-RAR; in
neural-lineage tumors FABP7-RXRα supports a stem-like state.
Reported outputs are stem-like phenotype, epithelial-mesenchymal
transition and migration. (D) Tumor microenvironment interactions.
Adipocyte-macrophage-tumor fatty acid shuttling, altered regulatory
and CD8+ T-cell function and
fatty-acid-oxidation-dominant metabolism with HIF-1α stabilization.
Arrows: dark blue, induction of a FABP or a downstream consequence,
with solid and dashed forms as defined above; red in (B),
FABP-dependent amplification of inflammatory output; dashed orange
in (D), fatty acid movement between adipocytes, macrophages and
tumor cells, where the dashed form denotes lipid movement rather
than evidence status. CRABPII, cellular retinoic acid-binding
protein II; DAMP, damage-associated molecular pattern; EMT,
epithelial-mesenchymal transition; FA, fatty acid; FABP, fatty
acid-binding protein; HIF-1α, hypoxia-inducible factor 1α; MCP-1,
monocyte chemoattractant protein 1; NLRP3, NLR family pyrin domain
containing 3; PPARβ/δ, peroxisome proliferator-activated receptor
β/δ; RA, retinoic acid; RAR, retinoic acid receptor; RXRα, retinoid
X receptor α; Th17, T helper 17; TME, tumor microenvironment; Treg,
regulatory T cell; UCP2, uncoupling protein 2.
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Copy and paste a formatted citation
Spandidos Publications style
Hah Y, Ju Y, Lee S, Hwang J and Kwag S: Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review). Int J Mol Med 58: 366, 2026.
APA
Hah, Y., Ju, Y., Lee, S., Hwang, J., & Kwag, S. (2026). Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review). International Journal of Molecular Medicine, 58, 366. https://doi.org/10.3892/ijmm.2026.6037
MLA
Hah, Y., Ju, Y., Lee, S., Hwang, J., Kwag, S."Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58.6 (2026): 366.
Chicago
Hah, Y., Ju, Y., Lee, S., Hwang, J., Kwag, S."Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58, no. 6 (2026): 366. https://doi.org/10.3892/ijmm.2026.6037
Copy and paste a formatted citation
x
Spandidos Publications style
Hah Y, Ju Y, Lee S, Hwang J and Kwag S: Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review). Int J Mol Med 58: 366, 2026.
APA
Hah, Y., Ju, Y., Lee, S., Hwang, J., & Kwag, S. (2026). Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review). International Journal of Molecular Medicine, 58, 366. https://doi.org/10.3892/ijmm.2026.6037
MLA
Hah, Y., Ju, Y., Lee, S., Hwang, J., Kwag, S."Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58.6 (2026): 366.
Chicago
Hah, Y., Ju, Y., Lee, S., Hwang, J., Kwag, S."Fatty acid‑binding proteins at the inflammation‑cancer interface: Isoform‑specific metabolic‑immune mechanisms and therapeutic implications (Review)". International Journal of Molecular Medicine 58, no. 6 (2026): 366. https://doi.org/10.3892/ijmm.2026.6037
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