Targeting Fat-Binding Proteins: How Fat Processing, Brain Inflammation, and Nerve Cell Damage Interact

This review was conducted based on a comprehensive literature search of the PubMed, Scopus, and Web of Science databases for articles published up to May 2025. The search strategy employed a combination of keywords and medical subject headings terms, including "Fatty Acid Binding Protein," "FABP," "neurodegeneration," "neuroinflammation," "Alzheimer's Disease," "Parkinson's Disease," "Multiple Sclerosis," "amyotrophic lateral sclerosis," "glial metabolism," "microglia," "astrocyte," "oligodendrocyte," "ferroptosis," "gut–brain axis," "LLPS," and the names of specific pharmacological agents such as "BMS309403," "MF6," "MF1," "HY08," and "ART26.12." We included peer-reviewed original research articles, meta-analyses, and comprehensive reviews written in English. The selection criteria prioritized studies that elucidated the molecular mechanisms of FABPs in the CNS, their role in the pathophysiology of NDDs, and the development and preclinical validation of FABP-targeted inhibitors.

Under physiological conditions, neurons and astrocytes consume most of the glucose in the brain [18]. However, in pathological states, activated microglia and astrocytes undergo metabolic reprogramming [19]. This reprogramming elevates glucose uptake and anaerobic glycolysis and activates the pentose phosphate pathway, while often maintaining mitochondrial function [20]. This metabolic shift supports the high energy and biosynthetic demands of activated glial cells and is tightly coupled to the amplification of inflammatory signaling [21].

FABP5 and FABP7 in astrocytes, and FABP4 in microglia, are key drivers of this "meta-inflammatory" axis. In inflammatory states, these glial cells shift from oxidative phosphorylation to glycolysis. FABP5 and FABP7 in astrocytes capture and deliver peripherally and locally sourced long-chain fatty acids (LCFAs) to provide biosynthetic precursors for rapidly proliferating cells. Concurrently, by delivering fatty acids into the nucleus, they bind to receptors such as PPARs, which deregulates their inhibition of NF-κB, and directly drives the transcription and secretion of pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 [4,22].

In microglia, FABP4 is now recognized as a core driver of neuroinflammation [23]. Its expression is critical for their inflammatory and metabolic responses to stimuli like lipopolysaccharide (LPS) [24]. The mechanism involves a classic signaling cascade where LPS binds to Toll-like receptor 4 (TLR4), leading to the recruitment of the adaptor protein MyD88 [25,26]. This initiates a downstream cascade involving TRAF6 and TAK1, which activates two major inflammatory pathways: the IKK complex, leading to the phosphorylation and degradation of IκB and subsequent nuclear translocation of NF-κB, and the MAP kinase pathway, leading to JNK phosphorylation and AP-1 activation [27]. Both NF-κB and AP-1 drive the transcription of genes encoding reactive oxygen species (ROS) and inflammatory cytokines. Critically, this process creates a self-amplifying positive feedback loop: NF-κB activation upregulates the expression of FABP4 itself, which in turn enhances TLR4 expression and JNK phosphorylation, thus perpetuating the inflammatory state [28].

Furthermore, FABP4 also acts via a FABP4-UCP2 axis, where FABP4 inhibition leads to an increase in uncoupling protein 2 (UCP2), thereby attenuating ROS production and neuroinflammation [29]. Thus, FABP4 serves as a critical bridge connecting systemic metabolic dysfunction to central neuroinflammation, acting as the molecular entity of "meta-inflammation" within the brain's resident immune cells (Figure 1).

Myelin, the lipid-rich sheath surrounding neuronal axons, is critical for rapid nerve impulse conduction. Its formation and repair play a crucial role in the normal function of the nervous system, and requires the rapid synthesis of a large number of lipids membranes in a short period of time, involving a variety of key molecules [30], a process heavily dependent on FABP5 and FABP7 [31]. These FABPs facilitate the efficient transport of LCFAs and cholesterol from astrocytes and plasma into oligodendrocytes [32,33].

The two isoforms play distinct but complementary roles in this process. FABP5 preferentially delivers saturated/monounsaturated fatty acids to the mitochondrial matrix. There, they undergo β-oxidation to generate acetyl-CoA, which fuels the TCA cycle and oxidative phosphorylation, thereby generating the massive amounts of ATP and NADPH required to power the energetically demanding process of myelin synthesis and to counteract oxidative stress [33]. In contrast, FABP7 is enriched in the myelin precursor membrane system, where it is directly involved in the assembly of phospholipids and sphingolipids and enhances mitochondrial biogenesis by interacting with PGC-1α to ensure that lipid synthesis is synchronized to match the energy requirements [34]. This division of labor—FABP5 for energy production and FABP7 for biosynthesis and coordination—is critical for efficient myelin formation (Figure 2).

When FABP5/7 expression or function is impaired, fatty acids accumulate abnormally in the cytoplasm and mitochondria, leading to mitochondrial lipid overload, decreased respiratory chain activity, and a collapse of the mitochondrial membrane potential, excess lipoyl-CoA further induces a ROS burst and lipid peroxidation, triggering the opening of the mitochondrial permeability transition pore (mPTP), and ultimately triggering apoptosis or iron death in oligodendrocytes [35]. Animal models revealed that mitochondrial swelling, myelin basic protein (MBP) deficiency, and apoptotic markers (cleaved-caspase3) were significantly increased in mitochondria of Fabp5/7 double-knockout mice in Cuprizone-induced demyelination lesions, whereas exogenous FABP5/7 overexpression or administration of the small-molecule inhibitor MF-6 restored mitochondrial homeostasis, reduced ROS, and promoted myelin regeneration [36]. Thus, FABP5/7 plays a role in the transport and metabolism of fatty acids and provides the necessary lipid raw materials for myelination, thereby influencing myelin formation and development.

The aggregation of misfolded proteins, such as α-synuclein (α-syn), is a central feature of many NDDs like Parkinson's disease (PD) and Multiple System Atrophy (MSA). α-syn is a 17 kDa protein with three binding structural domains, the N-terminal, hydrophobic, and C-terminal domains, and is enriched in aspartic acid and glutamic acid. α-syn binds to lipids to form a complex and facilitates the binding of α-syn to synaptic membranes that activate platelet-activating factor [37]. Epidemiological evidence of the molecular dynamics of α-syn and in vitro studies have suggested that disorders of lipid homeostatic disturbances may play a role in the pathogenesis of α-syn aggregation [38]. For a long time, FABPs were thought to exacerbate α-syn aggregation by promoting the formation of lipid droplets (LDs), which provide a hydrophobic surface for protein aggregation. However, this description can be deepened with the cutting-edge concept of LLPS, which is now considered a key mechanism driving the formation of membrane less organelles and the initiation of pathological protein aggregation [39,40].

The mechanistic logic is as follows: first, the biogenesis of LDs is itself driven by the LLPS of neutral lipids in the endoplasmic reticulum [41]. Second, and critically, the aggregation of key NDD-related proteins, including α-syn and tau, is now confirmed to be initiated via LLPS [40,42]. In this process, proteins first form liquid-like condensates that subsequently "mature" into irreversible, toxic solid-state aggregates. Therefore, the role of FABPs is far more than providing a passive "hydrophobic surface". They are very likely active regulators of the LLPS process itself. By precisely controlling the concentration and composition of specific fatty acids within the cell, FABPs directly modulate the thermodynamic environment of the cytoplasm, thereby promoting or inhibiting the phase separation of intrinsically disordered proteins like α-syn. This perspective elevates the role of FABPs from passive "accomplices" to "active regulators" of the first step in proteotoxicity, greatly enhancing their pathological significance.

Beyond generally influencing the lipid environment, specific FABPs can directly participate in the aggregation process [43,44,45]. For instance, recent research has uncovered a direct interaction between FABP7 and α-syn, demonstrating that they form hetero-aggregates which exhibit significantly higher neurotoxicity than α-syn aggregates alone [44]. This finding introduces a novel mechanism where FABP7 acts not just as a lipid transporter but as a direct co-factor in the formation of toxic protein species. Further investigation revealed that these highly toxic hetero-aggregates are selectively propagated into oligodendrocytes and Purkinje cells, the cell types most affected in MSA—via an epsin-2-dependent endocytosis pathway. This work provides a molecular basis for the cell-specific pathology in certain synucleinopathies and establishes FABP7 as a critical mediator linking lipid metabolism directly to the aggregation and cell-to-cell spread of α-syn.

The long-held view of NDDs as confined to the CNS is being challenged by the concept of the "gut–brain axis" [46]. A central tenet of this model is that pathology can originate in the periphery and spread to the brain [47]. In synucleinopathies like PD, compelling evidence suggests that misfolded α-syn first appears in the enteric nervous system (ENS) and propagates to the brainstem via retrograde axonal transport along the vagus nerve in a prion-like fashion [48].

The intestinal protein FABP2 plays a crucial, albeit indirect, role in initiating this cascade. FABP2 is vital for maintaining intestinal barrier integrity by regulating tight junction proteins [49]. In conditions of gut dysbiosis, often driven by poor diet or aging, FABP2 function can be impaired [49,50]. This leads to increased intestinal permeability, a condition known as "leaky gut". This barrier dysfunction has two critical consequences. First, it is thought to create a local inflammatory environment within the gut that promotes the initial misfolding and aggregation of α-syn in the ENS. Second, it allows bacterial endotoxins, particularly LPS, to leak from the gut lumen into the systemic circulation, causing chronic, low-grade systemic inflammation (Figure 3).

This systemic inflammation represents a "second hit" to the CNS. Circulating inflammatory molecules like LPS can compromise the integrity of the BBB, further promoting neuroinflammation. Once in the brain, LPS directly activates microglia via the FABP4/TLR4 signaling pathway described earlier [24,51], establishing a persistent neuroinflammatory state. This chronic inflammation creates a toxic environment that can exacerbate the neurodegeneration caused by the primary α-syn pathology spreading via the vagus nerve. Thus, the gut–brain-FABP axis represents a multi-faceted pathogenic model where peripheral FABP2 dysfunction initiates events in the gut, leading to both direct prion-like propagation of proteopathy and an indirect, systemic inflammatory response that is mediated centrally by FABP4 [49] (Figure 3). This highlights the utility of peripherally restricted inhibitors, which may succeed not by acting directly on the brain, but by cutting off this peripheral "fuel supply" for central inflammation.

Ferroptosis is a form of regulated, iron-dependent cell death driven by the overwhelming accumulation of lipid peroxides, particularly from polyunsaturated fatty acids (PUFAs) within phospholipids [52]. FABP's ferroptosis connection is novel, but recent research has unequivocally proven this connection.

FABP5 has been posited as a key driver of ferroptosis especially in the context of cerebral hypoxia, stroke and cancer [53,54]. Under cellular stress, FABP5 is upregulated and acts in a positive feedback loop, facilitating the transport and incorporation of PUFAs into cellular membranes. This enriches the membrane with lipids that are highly susceptible to peroxidation, thereby increasing the cell's vulnerability to ferroptotic death. In contrast, FABP7 has been identified as a protector against ferroptosis [55]. FABP7 actively sequesters vulnerable PUFAs, transporting them away from the cell membrane and into the relative safety of lipid droplets for storage. This mechanism effectively isolates PUFAs from the iron-dependent peroxidative machinery, shielding cells like astrocytes from ferroptotic death. This dichotomous regulation—FABP5 as a sensitizer and FABP7 as a protector—positions the FABP axis as a critical control point in the balance between cell survival and ferroptotic death (Figure 4 and Table 1).

The clinical application of FABP-targeted therapies is still constrained by the BBB which limits drug access to the CNS and complicates therapeutic delivery. Thus, the design of CNS drugs requires ligands that not only demonstrate high-affinity and isoform-selective FABP binding but also robust BBB permeation [97]. There is now a better ability to overcome these challenges due to advances in medicinal chemistry. These CNS penetrating FABP inhibitors can modulate lipid signaling, glial activation, and the neuroinflammatory processes in NDDs. The following sections discuss preclinical studies of select drugs of this class, and their rationale related to design, pharmacokinetics, as well as preclinical efficacy.

The successful development of ART26.12 provides a new approach for FABP-targeted therapy. ART26.12 is a third-generation selective inhibitor of FABP5 from the truxillic acid monoester series It exhibits high affinity for FABP5 (inhibition constant [Ki]: 0.77 ±0.08 μM) with markedly lower affinity for FABP3 (Ki: 71.32 ± 2.40 μM), FABP4 (Ki: > 100 μM), and FABP7 (Ki: 18.99 ± 1.81 μM), as determined by fluorescence displacement assay. By inhibiting FABP5-mediated trafficking of endocannabinoids such as anandamide, ART26.12 reduces their catabolism and enhances local endocannabinoid tone. This indirectly activates CB1 signaling, with potential contributions from CB2, TRPV1, and PPARα receptors involved in metabolic regulation and anti-inflammatory responses. Transcriptomic profiling in the periaqueductal gray revealed upregulation of ion channel and GABAergic synapse-related genes, suggesting central neurophysiological adaptations relevant to pain processing and lipid signaling [104]. These findings support ART26.12 as a mechanistically distinct FABP5-targeting compound that modulates both metabolic and inflammatory pathways implicated in neurodegenerative disease.

ART26.12 demonstrates favorable oral pharmacokinetics, with rapid absorption (Tmax ≈ 0.5 h at 10 mg/kg) and high bioavailability (163% at 300 mg/kg), suggesting nonlinear uptake or enterohepatic recirculation. [104]. Although CNS penetration is limited (brain-to-plasma ratio ≈ 2.3%), the compound reaches therapeutically relevant concentrations in the spinal cord (0.4 ± 0.1 μM), a key region for neuroimmune and metabolic integration in pain modulation [104,105]. ART26.12 is well tolerated in preclinical species, with a no observed adverse effect level (NOAEL) of 1000 mg/kg/day in both rodents and dogs [104].

ART26.12 has shown efficacy across multiple peripheral neuropathy models, including oxaliplatin-induced peripheral neuropathy (OIPN), paclitaxel-induced neuropathy (PIPN), streptozotocin-induced diabetic neuropathy, and cancer-induced bone pain. It dose-dependently reverses mechanical allodynia and cold hyperalgesia, preserves body weight during treatment [104,105]. In diabetic neuropathy models, ART26.12 outperformed duloxetine in reversing pain behaviors at earlier time points [105]. Mechanistically, its analgesic effects are mediated by FABP5-dependent endocannabinoid pathways, involving CB1 and PPARα signaling, both of which are associated with glial regulation and lipid-driven inflammation [104]. These results highlight ART26.12 as a lipid-targeting analgesic with potential utility in diseases involving neuroimmune dysregulation and metabolic dysfunction and strongly support the aforementioned "gut–brain axis" and systemic inflammation theories: even intervening in peripheral metabolic/inflammatory pathways can have a profound impact on the symptoms of the CNS (Table 2).

This review has emphasized the pivotal position of brain-expressed FABPs as key orchestrators of lipid metabolism, placing them at the nexus of metabolic reprogramming, neuroinflammation, and cell death in NDDs. The evidence provided here supports the conclusion that targeting FABP-mediated metabolic shifts in the brain indicates a primary intervention approach to treating NDDs.

As discussed, meta-inflammatory frameworks in glial cells as well as metabolic survival balance in oligodendrocytes rely heavily on FABP-driven lipid transport. The preclinical successes of the ligands discussed here lend strong support to this hypothesis. Molecules MF6, MF1, and HY08 demonstrate that CNS-penetrant compounds can directly influence critical metabolic pathways to rectify complex demyelinating and proteotoxic as well as ischemic injuries. At the same time, the peripherally restricted inhibitor ART26.12 shows that targeting FABP5 pathways, even outside the CNS, can deeply influence neuroinflammatory processes, underscoring the therapeutic importance of peripheral FABP5 in neuroimmune nexus disordered metabolism.

As a result, disparate FABPs can be regarded as active, multi-faceted therapeutic targets that can be utilized to reshape.

The attractive preclinical rationale for FABP inhibitors supports therapeutic avenues that are yet to be explored. Future FABP drug discovery will likely evolve from broad inhibition toward more precise strategies.

FABP drug discovery is likely to evolve beyond broad inhibition toward isoform-specific and cell-type-specific selectivity. Next-generation inhibitors may aim to differentially modulate FABP5 and FABP7 in disease-relevant glial populations, such as microglia, astrocytes, and oligodendrocytes, allowing cell-type-specific control of lipid metabolism and inflammatory responses. A promising direction involves integrating lipidomic data to guide ligand design. Integrating lipidomic profiling into FABP-targeted drug design may allow for the development of inhibitors that selectively block the trafficking of disease-relevant lipid species, offering a more tailored and mechanism-driven approach to therapy. Such approaches could enhance therapeutic efficacy and minimize off-target effects. Moreover, FABP isoforms and their lipid cargoes may serve as biomarkers for early diagnosis, patient stratification, and treatment monitoring.

FABP inhibitors act upstream of multiple pathological processes and are thus well suited for combination with agents that target downstream consequences. For instance, combining a FABP3 inhibitor like MF1, which suppresses α-syn oligomer formation, with agents that target aggregate clearance could provide a synergistic, dual-pronged therapeutic strategy. In demyelinating disorders, using MF6 in combination with a pro-myelinating compound could halt glial damage while promoting remyelination. Likewise, combining a peripherally restricted inhibitor like ART26.12 with a centrally acting analgesic may enable comprehensive pain control by addressing both peripheral and central sensitization. These combinatorial strategies may amplify therapeutic efficacy and broaden the clinical utility of FABP-targeted approaches.

Aberrant Post-Translational Modifications (PTMs) (e.g., phosphorylation, ubiquitination) are a hallmark of NDDs, altering protein function, localization, and aggregation. The function of FABPs themselves may be subject to such regulations. A critical unanswered question is whether FABPs undergo PTMs in NDDs. For example, could phosphorylation of FABP5 alter its binding to VDAC-1, or could ubiquitination of FABP7 target it for degradation, weakening its neuroprotective role in ferroptosis? Investigating the PTMs of FABPs opens a new research field and suggests novel therapeutic targets (e.g., inhibiting a kinase that phosphorylates a FABP), which could offer a more refined and specific strategy than broad ligand inhibition.

In summary, this review highlights the overlooked potential of FABPs as bridges within the networks of lipid metabolism, neuroinflammation, and cell death. Spanning from basic mechanisms to therapeutics, focusing on FABP-centric pathways presents a single and coherent approach to altering neurodegenerative processes. As the field moves forward, the comprehensive therapeutic prospects of FABP-targeted strategies in NDDs will require lipidomic, structural, and precision pharmacological interventions.